Eicosanoids derived from cytochrome P450 pathway of arachidonic acid and inflammatory shock

Prostaglandins and Other Lipid Mediators 145 (2019) 106377

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Eicosanoids derived from cytochrome P450 pathway of arachidonic acid and inflammatory shock

T

Bahar Tunctana, , Sefika Pinar Senola, Meryem Temiz-Resitoglua, Demet Sinem Gudena, Seyhan Sahan-Firata, John R. Falckb, Kafait U. Malikc ⁎

a

Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, Turkey Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA c Department of Pharmacology, College of Medicine, University of Tennessee, Center for Health Sciences, Memphis, TN, USA b

ARTICLE INFO

ABSTRACT

Keywords: Inflammatory shock Septic shock Animal models Arachidonic acid CYP-derived eicosanoids

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Septic shock, the most common form of vasodilatory shock, is a subset of sepsis in which circulatory and cellular/metabolic abnormalities are severe enough to increase mortality. Inflammatory shock constitutes the hallmark of sepsis, but also a final common pathway of any form of severe long-term tissue hypoperfusion. The pathogenesis of inflammatory shock seems to be due to circulating substances released by pathogens (e.g., bacterial endotoxins) and host immuno-inflammatory responses (e.g., changes in the production of histamine, bradykinin, serotonin, nitric oxide [NO], reactive nitrogen and oxygen species, and arachidonic acid [AA]-derived eicosanoids mainly through NO synthase, cyclooxygenase, and cytochrome P450 [CYP] pathways, and proinflammatory cytokine formation). Therefore, refractory hypotension to vasoconstrictors with end-organ hypoperfusion is a life threatening feature of inflammatory shock. This review summarizes the current knowledge regarding the role of eicosanoids derived from CYP pathway of AA in animal models of inflammatory shock syndromes with an emphasis on septic shock in addition to potential therapeutic strategies targeting specific CYP isoforms responsible for proinflammatory/anti-inflammatory mediator production.

Abbreviations: 2-AG, 2-Arachidonoyl-sn-glycerol; 5,14-HEDGE, N-(20-hydroxyeicosa-5[Z]14[Z]-dienoyl)glycine; AA, Arachidonic acid; ALI, acute lung injury; AP, activator protein; ASC, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain; CARS, compensatory anti-inflammatory response syndrome; CASP, colon ascendens stent peritonitis; CCI, chronic critical illness; CD, cluster of differentiation; CGRP, calcitonin gene-related peptide; CLP, cecal ligation and puncture; COX, cyclooxygenase; C. rodentium, Citrobacter rodentium; CRP, C-reactive protein; CYP, cytochrome P450; DAMP, damage-associated molecular pattern; DHET, dihydroxyeicosatrienoic acid; ECF, eosinophil chemotactic factor; eNOS, endothelial nitric oxide synthase; E. coli, Escherichia coli; EET, epoxyeicosatrienoic acid; ERK, extracellular signal-regulated kinase; HETE, hydroxyeicosatetraenoic acid; HR, heart rate; IB, inhibitor of B; ICAM, intracellular adhesion molecule; ICU, intensive care unit; IFN, interferon; IKK, inhibitor of B kinase; IL, interleukin; i.c.v., intracerebroventricular; i.p., intraperitoneal; i.v., intravenous; iNOS, inducible nitric oxide synthase; JAK, janus kinase; LOX, lipoxygenase; LPS, lipopolysaccharide; LT, leukotriene; LX, lipoxin; MAP, mean arterial blood pressure; MAPK, mitogen-activated protein kinase; MEK or MKK, mitogen-activated protein kinase kinase; miRNA, microribonucleic acid; MODS, multiple organ dysfunction syndrome; MOF, multiple organ failure; miRNA, micro messenger ribonucleic acid; mRNA, messenger ribonucleic acid; mTOR, mammalian target of rapamycin; MyD, myeloid differentiation factor; NADPH, nicotinamide adenine dinucleotide phosphate; NCF, neutrophil chemotactic factor; NF-κB, nuclear factorκB; NLR, nucleotide binding domain and leucine-rich repeat; NLRP3, nucleotide binding domain and leucine-rich repeat protein; NO, nitric oxide; NOS, nitric oxide synthase; NOX, nicotinamide adenine dinucleotide phosphate oxidase; PAF, platelet-activating factor; PAMP, pathogen-associated molecular pattern; PDGF, plateletderived growth factor; PG, prostaglandin; PICS, persistent inflammation-immunosuppression catabolism syndrome; PKG, protein kinase G; PON, peroxynitrite; PPAR, peroxisome proliferator-activated receptor; Pseudomonas aeruginosa, P. aeruginosa; RNA, ribonucleic acid; RNS, reactive nitrogen species; ROS, reactive oxygen species; RXR, retinoid X receptor; sEH, soluble epoxide hydrolase; sGC, soluble guanylyl cyclase; SIRS, systemic inflammatory response syndrome; Staphylococcus aureus, Staph. aureus; STAT, signal transducers and activators of transcription; TAK, transforming growth factor-activated kinase; TGF, tumor growth factor; TLR, tolllike receptor; TNF, tumor necrosis factor; TRAF, tumor necrosis factor receptor-associated factor; TIRAP, toll-interleukin-1 receptor domain containing adaptor protein; VCAM, vascular cell adhesion molecule; VSMCs, vascular smooth muscle cells ⁎ Corresponding author at: Department of Pharmacology, Faculty of Pharmacy, Yenisehir Campus, Mersin University, 33160, Yenisehir, Mersin, Turkey. E-mail address: [email protected] (B. Tunctan). https://doi.org/10.1016/j.prostaglandins.2019.106377 Received 21 April 2019; Received in revised form 6 September 2019; Accepted 18 September 2019 Available online 03 October 2019 1098-8823/ © 2019 Elsevier Inc. All rights reserved.

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1. Introduction

infectious and noninfectious stimuli (e.g., bacterial/viral infection, injury, trauma, surgery, burn, ischemia, chemical irritants, stress, or ionizing radiation) and acts by removing injurious stimuli and initiating the healing process [10,34–39]. As a powerful tool used by innate and adaptive immune systems to maintain cell and tissue homeostasis, inflammation is a dynamic process depending on the place (i.e., local or systemic), intensity (i.e., low, medium or high) and duration (i.e., acute or chronic). Acute inflammation has a rapid onset of minutes or hours, usually resolving in a few days [10,34–38]. During acute inflammatory responses, cellular and molecular events and interactions efficiently minimize impending injury or infection. Acute inflammation is an immediate, but a nonspecific response against pathogens or tissue injuries that promotes the recruitment of blood leukocytes (granulocytes [neutrophils, eosinophils, and basophils], monocytes, and lymphocytes [T cells and B cells]), stimulation of tissue-resident macrophages and mast cells, along with the production of mediators of inflammation and acute phase response. It is resolved and the tissue is repaired when pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), pathogens and damaged tissues are cleared, granulocyte recruitment ceases with a down-regulation and scavenging of chemokines, and recruited granulocytes are subsequently cleared by efferocytosis. An effective acute inflammatory response leads to resolution of the inflammation and tissue repair; however continuous damage or an unsuccessful acute response promotes the development of chronic inflammation. Chronic inflammation has a slow onset of days, a long duration of years, less prominent classical signs and symptoms, and cellular infiltrate primarily composed of monocytes/macrophages and lymphocytes. The progression from acute to chronic inflammation can take weeks or months depending on stimuli intensity and duration [10,34–39]. A variety of chemical mediators from the circulatory system, inflammatory cells, and injured tissue actively contribute to and adjust the inflammatory response (Table 1) [10,11,32,34–52]. The mediators include 1) proinflammatory (e.g., interleukin [IL]-1β, -2, -3, -6, -8, -12, -18, interferon [IFN]-γ, and tumor necrosis factor [TNF]-α) and antiinflammatory cytokines (IL-4, -10, -11, and tumor growth factor (TGF)β) [10,35–39]; 2) chemotactic factors (e.g., eosinophil chemotactic factor (ECF)-A, neutrophil chemotactic factor (NCF), platelet-activating factor (PAF), leukotriene [LT]-B4, and platelet-derived growth factor [PDGF]) [34–37], 3) acute phase proteins (e.g., C-reactive protein [CRP]) [38,39]; 4) endogenous cannabinoids (e.g., anandamide and 2arachidonoyl-sn-glycerol [2-AG]) [53]; 5) vasoactive amines (e.g., serotonin and histamine) [34,40]; 6) peptides (e.g., bradykinin) [34]; 7) adhesion molecules (e.g., E-selectin, P-selectin, intracellular adhesion molecule [ICAM]-1, vascular cell adhesion molecule [VCAM]-1) [10,34]; 8) neuropeptides (e.g., substance P and calcitonin gene-related peptide [CGRP]) [11], 9) resolvins (e.g., resolvin D2/E1) [50]; 10) RNS and ROS (e.g., NO, peroxynitrite [PON], and superoxide) [9,10,15,35,38,41,45,46]; and 11) COX- (e.g., prostaglandins [PGs] and thromboxane A2 [TxA2] [9,34,38,40,44,46,49,52], 5-,12-lipoxygenase (5-,12-LOX)- (e.g., leukotrienes, lipoxins (e.g., lipoxin [LX] A4 and LXB4) and hydroxyeicosatetraenoic acids [HETEs]) [9,34,38,44,46,49], and CYP-derived eicosanoids (e.g., 20-HETE and epoxyeicosatrienoic acids [EETs] produced by CYP ω-hydroxylases and CYP epoxygenases, respectively) [9,32,43,44,48,49,51]. Changes in the activity of nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathways [35,38,40,42] in addition to the expression of transcription factors (e.g. peroxisome proliferator-activated receptor [PPAR] α, PPARβ/δ, and PPARγ]) are also associated with inflammatory process [32,43,47]. Recent studies have implicated that the dysregulation of two pathways of genetically encoded necrotic cell death, pyroptosis (a specifically programmed cell death characterized by the release of inflammatory cytokines) and necroptosis (a lytic form of inflammatory cell death), in a variety of inflammatory conditions including sepsis and

In an inflammatory shock state, high rates of vasodilator mediator formation result in marked smooth muscle relaxation, pressor refractory vasodilation, and ultimately shock. Inflammatory shock constitutes the hallmark of sepsis, but also is the final common pathway of any form of severe long-term end-organ hypoperfusion and refractory hypotension [1–10]. In recent years, it has become well accepted that sepsis exhibits two, oftentimes concomitant, inflammatory stages: 1) a proinflammatory phase, referred to as the systemic inflammatory response syndrome (SIRS), and 2) an anti-inflammatory phase, called "compensatory anti-inflammatory response syndrome (CARS)" with multiple organ failure (MOF) [1,4–7,9–14]. The events that lead to inflammatory shock are multifactorial and not yet fully understood. The pathogenesis of inflammatory shock syndromes such as septic shock seems to be due to circulating substances released by pathogens (e.g., bacterial endotoxins) and host immuno-inflammatory responses (e.g., changes in the production of histamine, bradykinin, serotonin, and proinflammatory cytokines as well as nitric oxide [NO], reactive nitrogen and oxygen species [RNS and ROS], and eicosanoids generated through mainly NO synthase [NOS], nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, cyclooxygenase [COX], and cytochrome P450 [CYP] pathways) [1,3,6,9,10,15,13–22]. According to the new definitions of sepsis and septic shock (Third International Consensus Definitions for Sepsis and Septic Shock [Sepsis3]) developed in 2016, sepsis is now defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection, and septic shock is a subset of sepsis in which circulatory and cellular/ metabolic abnormalities are severe enough to increase mortality [23]. Recent epidemiological studies showed that the incidence of sepsis had been steadily growing over the past three decades and the burden of sepsis has been reported worldwide. According to the most recent Center for Disease Control report, it is estimated that sepsis affects at least 1.7 million adults in America annually, causing the death of 270,000 individuals and being responsible for one of three patients dying from sepsis [24]. Therefore, sepsis has recently been recognized by the World Health Organization as a global health priority [25]. The treatment of sepsis can include fluid resuscitation, antimicrobial therapy, vasoactive medications, corticosteroids, blood products, and mechanical ventilation when necessary [23]. The cost of each case of sepsis differs based on the absence or presence of septic shock as well as patient comorbidities and other patient-specific considerations. The overall cost of sepsis reflects not only the price of initial hospitalization, but also the postdischarge care costs, including post-sepsis syndrome and functional/cognitive disabilities that require a significant amount of healthcare resources [26]. Despite intensive basic research worldwide and numerous clinical trials, there are currently no effective pharmacological treatment approaches for sepsis and septic shock. The lack of effective treatments is due partly to our continuing incomplete understanding of sepsis physiopathology as well as the difficulty of conducting experiments on critically ill patients and use of inappropriate experimental models [2,3,13,27–31]. New emerging drugs focused on modifying the inflammatory response are currently being investigated for the treatment of septic shock [13,18,30,32,33]. Therefore, in this review, we will present a brief overview of inflammation and inflammatory shock. We will also summarize current knowledge regarding the role of eicosanoids derived from CYP pathway of arachidonic acid (AA) in animal models of inflammatory shock syndromes with an emphasis on septic shock. Finally, we will address potential therapeutic strategies targeting specific CYP isoforms responsible for proinflammatory/anti-inflammatory mediator production in inflammatory shock states. 2. Inflammation Inflammation is an adaptive immune system response to harmful 2

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Table 1 Summary of chemical mediators from the circulatory system, inflammatory cells, and injured tissue actively contributing to and adjusting the inflammatory response. Chemical Mediators Cytokines [10,35,36,37,38,39,40] IL-1β, -2, -3, -6, -8, -12, -18, IFN-γ, and TNF-α IL-4, -10, -11, and TGF-β Chemotactic factors [34,35,36,37] ECF-A NCF PAF

Main Sources

Main Functions

Monocytes/macrophages, neutrophils, T cells, natural killer cells, CD4+ lymphocytes, adipocytes, epithelial cells, endothelial cells, dendritic cells, etc. Monocytes/macrophages, lymphocytes, fibroblasts, neurons, epithelial cells, etc.

Proinflammation; apoptosis, proliferation, differentiation, cytokine production, chemotaxis, angiogenesis, activation of natural killer cells, and innate/adaptive immunity Anti-inflammation; inhibition of the proinflammatory cytokines, proliferation, differentiation, and induces acute phase protein

Mast cells Macrophages Platelets, granulocytes, monocytes/macrophages, lymphocytes, mast cells, endothelial cells, etc.

Inflammation; eosinophil chemotaxis Inflammation; neutrophil chemotaxis Inflammation; eosinophil chemotaxis, vasoconstriction, vasodilation and vascular leakage at low PAF concentrations, bronchoconstriction, platelet activation, apoptosis, and angiogenesis Inflammation; neutrophil chemotaxis, vascular leakage, and enhanced epithelial barrier function Inflammation; cell division and proliferation

LTB4

Monocytes, granulocytes, lymphocytes, etc.

PDGF Acute phase proteins (e.g., CRP) [38,39] Native CRP

Platelets, vascular endothelial cells, pericytes, Kupffer cells, etc.

Monomeric CRP Endogenous cannabinoids [42] Anandamide 2-AG Vasoactive amines and peptides [34,40] Serotonin Histamine Bradykinin Adhesion molecules [10,33] E-selectin

Hepatocytes, smooth muscle cells, macrophages, endothelial cells, lymphocytes, adipocytes, etc. Hepatocytes, smooth muscle cells, macrophages, endothelial cells, lymphocytes, adipocytes, etc.

Anti-inflammation; inhibition of complement activation

Brain neurons Brain neurons

Anti-inflammation Proinflammation/anti-inflammation

Mast cells, platelets, etc. Mast cells, basophils, platelets, etc. Mast cells, kidney, pancreas, salivary glands, etc.

Inflammation; vasodilation and vascular leakage Inflammation; vasodilation and vascular leakage Inflammation; vasodilation and vascular leakage

Endothelial cells

Inflammation; adhesion of neutrophils, monocytes, and T cell subsets Inflammation; adhesion and rolling of platelets and leukocytes to areas of inflammation Inflammation; facilitate transendothelial migration of leukocytes

P-selectin

Endothelial cells and platelets

ICAM-1

Leukocyte, endothelial cells, platelets, fibroblasts, epithelial cells, glial cells, etc. Endothelial cells

VCAM-1 Neuropeptides [11] Substance P CGRP

Neurons, macrophages, eosinophils, lymphocytes, dendritic cells, etc. Neurons and neuroendcrine cells

Resolvins (e.g., resolvins D2/E1) [50]

Polymorphonuclear neutrophils, macrophages, etc.

RNS and ROS [9,10,15,35,38,41,45,46] eNOS-derived NO

iNOS-derived NO

nNOS-derived NO PON formed by the reaction of NO and superoxide COX-derived eicosanoids [9,34,38,40,44,45,49,52] PGD2 PGE2 PGF2α PGI2 TxA2 5-,12-LOX-derived eicosanoids [9,34,38,44,46,49] LTC4/LTD4/LTE4

Proinflammation; monocyte chemotaxis and the recruitment of circulating leukocytes

Inflammation; transmigration of monocytes and eosinophils Inflammation; regulation of smooth muscle contractility, epithelial ion transport, and vascular leakage Inflammation; inhibition of capacity of macrophages and dendritic cells to produce inflammatory cytokines Anti-inflammation; limitation of neutrophil infiltration and migration

Vascular endothelial cells, endocardial/myocardial cells, megakaryocytes, platelets, monocytes, neutrophils, neuronal cells, astrocytes, natural killer cells, lymphocytes, smooth muscle cells, hepatocytes, bone marrow cells, epithelial cells, etc. Vascular endothelial cells, VSMCs, endocardial/myocardial cells, epithelial cells, platelets, macrophages, neutrophils, eosinophils, lymphocytes, leukocytes, mast cells, dendritic cells, neuronal cells, astrocytes, microglial cells, Schwann cells, mesengial cells, hepatocytes, lipocytes, epithelial cells, fibroblasts, skeletal muscle cells, etc. Cerebellum, spinal cord, astrocytes, sympathetic ganglia, nitrergic nerves, skeletal muscle cells, adrenal gland, myocytes, epithelial cells, VSMCs, etc. Monocytes/macrophages, granulocytes, endothelial cells, etc.

Proinflammation/anti-inflammation; regulation of proinflammatory molecule expression, control of blood vessel tone and hemostasis, inhibition of platelet aggregation, angiogenesis, remodelling, mobilization of endothelial progenitor cells, and leukocyte adhesion Inflammation; vasodilation and cytotoxicity

Mast cells, brain, airways, etc.

Inflammation/anti-inflammation; vasodilation, vascular leakage, bronchoconstriction, and anti-aggregation Inflammation; vasodilation and vascular leakage

Macrophages, vascular smooth muscle cells, fibroblasts, platelets, brain, kidney, etc. VSMCs, airways, etc. Endothelial cells, platelets, kidney, brain, etc. Platelets, VSMCs, macrophages, kidney, etc. Eosinophils, monocytes, mast cells, etc.

Inflammation; vasodilation, central regulation of blood pressure, neurotransmission, and neurogenesis Inflammation; protein oxidation and nitration, lipid peroxidation, mitochondrial dysfunction, and cell death

Anti-inflammation; vasodilation/vasoconstriction Inflammation; vasodilation and anti-aggregation Inflammation; platelet aggregation and vasoconstriction Inflammation; vasoconstriction/vasodilation, vascular leakage, and bronchoconstriction

(continued on next page) 3

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Table 1 (continued) Chemical Mediators

Main Sources

Main Functions

LXA4/LXB4

Macrophages, neutrophils, etc.

HETEs

Monocytes/macrophages, neutrophils, eosinophils, mast cells, B cells, dendritic cells, etc.

Anti-inflammation; inhibition of neutrophil adhesion and chemotaxis and PON formation at the site of inflammation resulting in attenuation of accumulation of NF-κB and AP-1 in the nucleus Inflammation; leukocyte chemotaxis

CYP-derived eicosanoids [9,32,43,44,48,49,51] 20-HETE

Kidney, heart, liver, brain, lung, vasculature, etc.

EETs

Liver, intestine, heart, brain, lung, vasculature, etc.

NF-κB [35,38,40,42]

Macrophages, neutrophils, B cells, endothelial cells, VSMCs, heart, lung, kidney, neurons, glial cells, dendritic cells, Schwann cells, etc. Macrophages, neutrophils, fibroblasts, epithelial cells, VSMCs, heart, lung, kidney, etc.

MAPK and JAK/STAT [35,38,40,42] Transcription factors [32,43,47] PPARα PPARβ/δ PPARγ

Monocytes/macrophages, endothelial cells, VSMCs, kidney, heart, adipose tissue, etc. Endothelial cells, VSMCs, kidney, heart, brain, skeletal muscle, adipose tissue, etc. Monocytes/macrophages, endothelial cells, vascular smooth muscle cells, kidney, heart, intestine, adipose tissue, etc.

Inflammation/anti-inflammation; vasodilation/vasoconstriction and autoregulation of cerebral blood flow Anti-inflammation; vasodilation, inhibition of NF-κB activity, and activation of PPARs and a cation channel, transient receptor potential vanilloid 4 Inflammation; increased formation of adhesion molecules, chemokines, proinflammatory cytokines, NO, and PGs Inflammation; increased formation of proinflammatory cytokines, NO, and PGs Anti-inflammation; vasoprotection and inhibition of NF-κB activity and proinflammatory cytokine production Inflammation/anti-inflammation; inhibition of anti-inflammatory cytokine formation as well as NF-κB activity and proinflammatory cytokine production Anti-inflammation; vasoprotection and inhibition of oxidative stress and lymphocyte chemotaxis

vasoplegic, vasogenic, or distributive shock, includes a range of conditions associated with decreased systemic vascular resistance and altered oxygen extraction (it may be inflammatory, neurogenic, or anaphylactic). In vasodilatory shock, systemic vasodilation leads to decreased blood flow to the brain, heart, and kidneys causing damage to vital organs [3,67–71]. Refractory vasodilatory shock develops from uncontrolled vasodilation and vascular hyporesponsiveness to endogenous vasoconstrictors, causing the failure of physiologic vasoregulatory mechanisms [3–7,12,31]. Vasodilatory shock is the final common pathway for all forms of severe shock with sepsis the most common primary etiology and the leading cause of critical illness-related mortality. Due to the complexities of this disease, the causes and treatments for vasodilatory shock are multimodal [3–9,12,13,27–31,71–75]. The most common causes of vasodilatory shock in the intensive care unit (ICU) is sepsis [71]. Vasodilatory shock as a result of sepsis occurs due to a dysregulated immune response to bacterial, viral, fungal, or parasitic infections that leads to systemic cytokine release and resultant vasodilation and fluid leak from capillaries. The inflammatory cytokines can also cause some cardiac dysfunction, called "septic cardiomyopathy", which can contribute to the shock state [71]. Septic shock, the most severe complication of sepsis and carries a high mortality, is the most common form of vasodilatory shock [3,67–71]. Multiple organ systems are affected by sepsis and septic shock. MODS is defined as the failure of two or more organ systems in the acutely ill patient such that homeostasis cannot be maintained without intervention. Many risk factors predisposing to MODS; however, the most common risk factors are shock due to any cause, sepsis, or tissue hypoperfusion. MODS may originate from the increased vascular permeability induced by circulating cytokines, leading to inflammatory mediators leaking to different tissues, and initiating a new local inflammatory process, with increasing impairment of tissue functions [4,10,12,76]. With advances in intensive care, late MODS has decreased, however, a new entity termed "persistent inflammation-immunosuppression catabolism syndrome (PICS)" has been postulated as the underlying pathophysiology of chronic critical illness (CCI) [10]. PICS is proposed as a diagnosis for patients who have a prolonged stay in the ICU with controllable organ dysfunctions, protein catabolism,

septic shock [54–58]. During the inflammatory process, activation of inflammasomes such as canonical nucleotide binding domain and leucine-rich repeat (NLR) protein 3 (NLRP3) is also reported to be an important regulator of the release of proinflammatory cytokines IL-1β and IL-18 and induction of death of immune cells via pyroptosis or necroptosis [18,59–63]. Furthermore, certain microribonucleic acids (miRNAs), endogenous noncoding small ribonucleic acids (RNAs) and regulators of ICAM and VCAM through two distinct primary mechanisms, via modulating the proinflammatory NF-κB pathway, which controls their transcription, and directly targeting them, are reported to be involved in inflammation-associated diseases such as sepsis and septic shock [64,65]. Since acute and chronic inflammation-mediated tissue injury is observed in many organ systems, including the heart, pancreas, liver, kidney, lung, brain, intestinal tract, and reproductive system, the chronic inflammation in particular has a key role in the development and progression of diseases associated with inflammation such as cardiovascular, metabolic, neurodegenerative, renal, hepatic, respiratory, and rheumatic diseases [3,10,34,35,37,38,66,67]. 3. Inflammatory shock The concept of critical illness includes the definitions of shock, multiple organ dysfunction syndrome (MODS), MOF, acute respiratory failure, or cardiac/respiratory arrests, situations at imminent risk of death by generalized hypoxia. Shock is defined as the failure of the circulatory system to maintain adequate perfusion of vital organs. There are practically three categories of shock [3,4,12,67–71]: 1) cardiogenic; 2) hemorrhagic; and 3) inflammatory, which can be subdivided in septic and toxic shock. It is usually classified on the basis of the cause: 1) hypovolemic shock occurs as the result of reduced intravascular volume (it may be hemorrhagic or nonhemorrhagic); 2) cardiogenic shock occurs due to pump failure, most commonly as a consequence of severe postoperative myocardial stunning or secondary to a large anterior myocardial infarction; 3) obstructive shock refers to the presence of a mechanical obstruction to cardiac function including the terms tension pneumothorax, cardiac tamponade, and severe valvular obstruction, and 4) vasodilatory shock, also known as 4

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poor nutritional status and wound healing, immunosuppression, and recurrent infections. It is initiated by an early genomic and cytokine storm in response to microbial invasion during the initial phase of sepsis [10,76,77]. Although there are several nonspecific therapies for the prevention and resolution of MODS, mostly care is supportive. Clinical trials with agents to prevent inflammation have also generally failed to improve the outcomes in patients with MODS. On the other hand, considering that therapeutic approaches designed to alleviate the proinflammatory septic response have generally failed, much recent research has focused on understanding how and why septic patients display immunosuppressive characteristics, what the significance of septic immunosuppression may be and if there exist any therapeutic targets within the CCI, CARS, PICS, and MODS [10,76,77]. Therefore, the concept of the pathogenesis of inflammatory shock explains many limitations of current therapies [1,2,7,8,23,27–29,31,70,72,73,78–82] and may foster the development of new interventions to mitigate mainly the effects of overproduced vasodilator and proinflammatory mediators in this syndrome [30,33,60,61]. Unfortunately, there are currently no effective pharmacological treatments for septic shock, making early recognition, resuscitation, and immediate treatment with suitable antibiotics the key to reducing the burden of resulting disease. The current management of sepsis and septic shock includes antimicrobial agents to handle the underlying infection, optimization of intravascular volume to improve stroke volume, vasopressors to counteract the vasodilatory shock, organ support including hemodynamic stabilization to ensure rapid restoration of an adequate perfusion pressure to limit development and worsening of organ dysfunction, and high-quality supportive care [1,2,7,8,23,27–29,31,70,72,73,78–82]. In recent years, proper treatment combined with novel therapeutic approaches are the main tools used to continue decreasing the impact of sepsis and septic shock [1,2,4–8,13,20,23,27–31,33,60,61,70,72,73 ,78–82]. The Surviving Sepsis Campaign Guidelines are also constantly updated and included greater evidence-based recommendations for the treatment of sepsis in attempts to reduce sepsis-associated mortality [29]. Despite the huge expenditure of time and resources on the evaluation of new drugs for the treatment of sepsis and septic shock, little success has been achieved. New emerging drugs that focus on modifying the inflammatory response are currently being investigated for the treatment of septic shock. Immunomodulatory therapy for sepsis and septic shock includes inflammatory cytokines, cellular receptors, nuclear transcription factors, coagulation activators, and regulators of apoptosis/pyroptosis/necroptosis. There are also various therapeutic approaches based on monoclonal antibodies that block inflammatory mediators and their receptors, agents that block or eliminate bacterial products, and modulators of expression of certain miRNAs (e.g., miR143, miR-145, miR-146a, miR-150, miR-155, miR-182, and miR-584) [8,13,28,30,56,60,61,65,81]. They have shown promising results in animal tests and are currently at various stages of clinical trials.

-4A12b, and -4A14 are expressed in mice, however, only CYP4A12a metabolizes arachidonic to 20-HETE. 20-HETE is metabolized by alcohol dehydrogenase to the carboxylic acid which undergoes further metabolism by β-oxidation. 20-HETE is also a substrate for epoxygenases, LOXs, and COXs [9,17,43,49,83–85,92]. EETs are synthesized predominantly by CYP epoxygenases of the CYP2 family, including the 2C and 2 J classes, expressed particularly in the liver, intestine, heart, brain, lung, and vasculature. Some other mammalian CYP isoforms have also been reported to generate EETs (e.g., CYP1A, -2B, and -2D). Soluble epoxide hydrolase (sEH), expressed in all the organs investigated including, but not limited to liver, kidney, brain, stomach, intestines, pancreas, prostate, heart, lung, and skin, is the enzyme responsible for conversion of EETs to less active dihydroxyeicosatrienoic acids (DHETs) [32,43,52,83,84,86–91,93,94]. Although EETs exhibit a broad spectrum of anti-inflammatory activity against acute and chronic inflammation, 20-HETE has been reported to have both proinflammatory and anti-inflammatory properties in various animal models of inflammation. Accordingly, CYPs, responsible for production of 20-HETE and EETs, are thought to play an important role in the activation, suppression, and resolution of inflammation [9,17,32,43,46,49,52,83–87,89–91,93,95]. New compounds that act as 20-HETE and EET mimetics and antagonists in addition to inhibitors of CYP ω-hydroxylase, CYP epoxygenase, and sEH enzymes have also been synthesized and extensively examined in preclinical studies for indications such as inflammation. More recently, pharmacological agents directed at the CYP pathway have made their way to clinical trials; however, none have yet to be approved for human use [9,86,92–95]. Studying inflammatory shock states in humans is difficult for many reasons, including the complexity of the disease, the heterogeneous nature of the population and the lack of clearly defined biomarkers to make a diagnosis in addition to other factors associated with clinical research. Because of these difficulties, the use of animal models has been proposed as a valuable tool in the study of inflammatory shock. Animal models of inflammatory shock present unique features that make them ideal to further elucidate mechanisms of disease and to identify pathways that could become potential targets for treatment. On the other hand, there is no single ideal model of inflammatory shock states, particularly septic shock, but rather a large number of complementary models that iterate some discrete features of the disorders while minimizing others [11,96–101]. On the basis of the initiating agent, the nonsurgical and surgical murine models of inflammatory shock most widely used in preclinical research can be divided into mainly three categories (Table 2): 1) exogenous administration of a toxin (such as intraperitoneal [i.p.] or intravenous [i.v.] injection of lipopolysaccharide [LPS] or zymosan) [11,66,96–103]; 2) exogenous administration of a viable pathogen (such as infusion of live bacteria, i.p. implantation of fibrin clot impregnated with viable bacteria, and cecal slurry injection) [11,66,100,101]; and 3) disruption of the animal's endogenous protective barrier allowing for bacterial invasion (cecal ligation and puncture [CLP] and colon ascendens stent peritonitis [CASP]) [11,66,96–101,103]. These animal models resemble most of the clinical signs and laboratory findings commonly observed in humans with septic shock. However, each have their limitations, therefore, none of them is perfect for reestablishing the clinical conditions of septic shock. Method used to induce sepsis and septic shock, dose regimen, use of adjuvant/supportive therapy, species, age, gender, comorbidity, and mortality are the most critical factors that have a significant impact on determining a particular animal model's clinical relevance and translational power [11,66,96–103]. In the following sections, we will review the recent observations from our laboratory and others regarding the role of eicosanoids derived from CYP pathway of AA in the animal models of inflammatory shock states which are frequently used and try to address potential therapeutic strategies targeting specific CYP isoforms responsible for proinflammatory/anti-inflammatory mediator production in septic shock.

4. Eicosanoids derived from CYP pathway of AA in inflammatory shock AA, a 20-carbon ω-6 polyunsaturated fatty acid, is metabolized into several metabolites known as "eicosanoids". Eicosanoids generated from three enzymatic pathways, COX, LOX, and CYP, are key mediators of the inflammatory cascade. Two primary enzymatic pathways, CYP ωhydroxylase and CYP epoxygenases, are responsible for the production of CYP-derived eicosanoids from AA, mainly 20-HETE and EETs [9,16,32,43,49,83–91]. 20-HETE is an ω-hydroxylation product of AA that is produced mainly by the CYP4A and −4 F isoforms in the kidney, heart, liver, brain, lung, and vasculature. CYP4A11, -F2, and -F3 are the isoforms producing 20-HETE in humans. CYP4A1, -4A2, -4A3, -4A8, −4 F1, and −4 F4 are the corresponding isoforms in rats. CYP4A10, -4A12a, 5

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Table 2 Summary of the nonsurgical and surgical murine models of septic shock most widely used in preclinical research. Type of Model

Examples

Strengths

Limitations

Nonsurgical Exogenous administration of a toxin [11,66,96,97,98,99,100,101,102,103]

Injection (i.p. or i.v.) of LPS or zymosan

Simple and fast to learn and perform Accompanied by a notable systemic and central inflammation LPS is convenient to use and doses of LPS are readily measured Trimodal response to zymosan with resulting chronic, low-grade inflammation and organ failure Useful to test the efficacy of antiinflammatory strategies

Infusion (i.v. or i.p.) of live bacteria (such as E. coli, P. aeruginosa, Staph. aureus, or C. rodentium)

Technical ease Involves a single organism which can be selected by the researcher Reproduces several features of septic shock Helps understand host antibacterial mechanisms May be appropriate to study the blood clearance kinetics of organisms

Implantation of fibrin clot impregnated with viable bacteria

Allows for a controlled number of bacteria to be implanted, making it reproducible and reducing early mortality Promotes development of local septic focus Can be performed in neonatal mice Polymicrobial sepsis

Single toxin may not mimic responses in human sepsis Bypasses host-pathogen interactions Higher doses required in animals to produce a shock-like state Variable hemodynamic responses with different doses and infusion rates Short-lived inflammatory response Route of administration, doses of LPS and host species and strains may affect host responses to LPS Often does no lead to colonization and replication of bacteria Large doses of bacteria needed to breach host defenses Responses may vary between bacterial strains Variable host response dependent on bacterial load and infusion time Genetic background affects host responses to specific pathogens Infection of different compartments can alter host response High mortality rates without fluid resuscitation and antibiotic administration Significant inter-laboratory variability Surgery is required to insert clot Involves single bacteria strain, whereas human intraabdominal sepsis is often polymicrobial

Exogenous administration of a viable pathogen [11,66,100,101]

Cecal slurry injection

Surgical Disruption of the animal's endogenous protective barrier allowing for bacterial invasion [11,66,96,97,98,99,100,101,103]

CLP

Simple and easy surgical procedure Relatively reproducible No need to prepare and quantitate bacteria Bears an obvious resemblance to clinical conditions Considered the gold standard for sepsis Multiple bacterial strains Severity can be controlled by the size of puncture Induce diffuse peritonitis with persistent systemic inflammation Resembles organ dysfunction that occurs in humans Severity can be controlled through a stent size

CASP

4.1. Eicosanoids derived from CYP pathway of AA in LPS-induced inflammatory shock

No component of tissue necrosis Inflammation does not persist as long as CLP or CASP Only helpful to study early inflammation and innate response Multiple confounding factors: Interlaboratory and inter-operator variability, length of caecum ligated, needle size, age, sex, strain, and necrosis Multiple bacterial flora Minor systemic inflammation Difficult to control bacterial load (amount of stool squeezed into peritoneum) and the magnitude of sepsis challenge More challenging surgical procedure and requirement for careful surgical techniques More difficult to perform than CLP Technically more challenging in comparison to CLP Multiple bacterial flora Load of stool transferred into peritoneum may be a confounding variable of CASP No component of tissue necrosis Mortality rate varies with stents of different diameters

lipoproteins, and polysaccharides in addition to LPS [104]. The lipid A part of LPS, also known as "endotoxin", is recognized as the most potent microbial mediator implicated in the pathogenesis of septic shock. "Endotoxic shock", "endotoxin shock", or "toxic shock" is septic shock due to the release of endotoxins during the destruction of Gram-negative bacteria, such as Escherichia coli (E. coli) [105,106].

LPS, a well-known PAMP, is a purified macromolecular glycolipid extracted from the cell walls of Gram-negative bacteria, whereas endotoxins contain small amounts of cell wall proteins, lipids, 6

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Fig. 1. Schematic diagram showing the involvement of MyD88/TAK1/IKKβ/IκB-α/NF-κB and MyD88/TAK1/MEK1/ERK1/2/AP-1 pathways in addition to PPARα/ β/γ and NLRP3 inflammasome that are responsible for changes in production of vasoactive and pro-/anti-inflammatory mediators (i.e., NO, RNS, ROS, PGs, 20-HETE, EETs, and LTB4) by certain enzymes (i.e., iNOS, NADPH oxidase, COX-2, CYP4A1, CYP2C23, and CYP4F6) and formation of proinflammatory cytokines (i.e., IL-1β, IL-8, and TNF-α) in the LPS-induced vascular hyporeactivity, hypotension, tachycardia, inflammation, tissue injury, MODS, MOF, and mortality based on the results of the current study and our previous findings [113–132]. (↑), increase; (↓), decrease.

LPS-induced systemic inflammation response is reported to be involved in the release of proinflammatory mediators to the circulation. These mediators augment the molecular and cellular responses associated with inflammation resulting in the injury of several organs, primarily kidney, heart, lung, and brain, associated with inflammation. Two different recognition systems, myeloid differentiation protein-2/ toll-like receptor (TLR) 4 and LPS-sensing cytosolic caspases, together confer responsiveness to LPS at the host cell surface, within endosomes, and in the cytosol [9,59,60,107–111]. Stimulation of host cells by LPS occurs through a series of interactions with several proteins such as LPS-binding protein, opsonic receptor cluster of differentiation (CD) 14, myeloid differentiation factor (MyD)-2, and TLR 4 [9,107,109,110,112]. Mammalian TLRs can function via MyD88-dependent (canonical) or -independent (noncanonical) pathways. The binding of a ligand to TLR1, -2, -4, -5, -6, -7, -8, -9, and -10 results in the activation of the MyD88-dependent pathway while TLR3 activates the MyD88-independent pathway. In contrast to most TLRs which signal exclusively through one of the two pathways, TLR4 can activate both MyD88-dependent and MyD88-independent signalling. TLR3 and TLR4 act via MyD88-independent pathways with delayed activation of NF-κB signaling. In the MyD88-dependent pathway, following the recognition of LPS, activation of inhibitor of κB (IκB) kinase (IKK) and MAPK pathways through TLR4/toll-IL-1 receptor domain containing adaptor protein (TIRAP)/IL-1 receptor-associated kinase 1/4/TNF receptor-associated factor (TRAF) 6/transforming growth factor-activated kinase (TAK) 1 cascade results in phosphorylation and degradation of IκB

proteins by IKKs. Subsequent nuclear translocation of NF-κB, and induction of another transcription factor, activator protein (AP)-1, by MAPKs (mitogen-activated protein kinase kinase [MEK or MKK] 1, MAPK kinase 3/6, MKK4, extracellular signal-regulated kinase [ERK] 1/2, p38 MAPK, and c-jun N-terminal kinase 1/2), respectively, results in increased production of proinflammatory mediators produced in certain cells, such as blood-borne cells (e.g. platelets, neutrophils, granulocytes, monocytes, and macrophages), vascular smooth muscle cells (VSMCs), and endothelial cells resulting in inflammation. These include eicosanoids, cytokines, RNS, and ROS. In the MyD88-independent pathway, following CD14-dependent internalization into the endosomes, toll-IL-1 receptor domain-containing adapter-inducing IFNβ-related adaptor molecule and TRIF are recruited to TLR4 before activating TRAF3. Activation of TRAF3 activates TBK1 and IKKε, which phosphorylate and activate the transcription factor IRF3 that stimulates a type I interferon response, and also mediates the production of proinflammatory cytokines in delayed signaling through endocytosis mechanisms [9,40,59,60,107–114]. In our previous studies, we have demonstrated that LPS (E. coli LPS, O111:B4; 10 mg/kg; i.p.) injection to rats produces a fall in mean arterial blood pressure (MAP) and an increase in heart rate (HR) over the 4 h course of the experiment. These changes reached a maximum of 4 h after LPS administration were associated with vascular hyporeactivity to norepinephrine in the isolated aorta and superior mesenteric artery [115–134]. In the kidney, heart, thoracic aorta, superior mesenteric artery, lung, liver, brain, and spleen of LPS-treated rats, we observed a 7

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decrease in the messenger ribonucleic acid (mRNA) and/or protein expression of CYP2C23, CYP4A1, and CYP4F6 in addition to production of proinflammatory/anti-inflammatory and vasodilator/vasoconstrictor eicosanoids (i.e., EETs and 20-HETE) [115,116,125,128–132,134]. The LPS-induced changes in the serum and/or tissues of endotoxemic rats were associated with: 1) decreased expression of endothelial NOS (eNOS) PPARα/β/γ and retinoid X receptor (RXR) α, and PPARα/β/γRXRα heterodimer formation [115,116,122]; 2) activation of MyD88/ TAK1/IKKβ/IκB-α/NF-κB and MyD88/TAK1/MEK1/ERK1/2/AP-1 pathways as well as expression/activity of sEH and mammalian target of rapamycin (mTOR) associated with importin-α3 protein expression [117,118,120,121,123,126,130,132] 3) increased expression/activity of inducible NOS (iNOS), soluble guanylyl cyclase (sGC), protein kinase G (PKG), COX-2, NADPH oxidase (NOX) subunits (NOX2 [gp91phox; a O2− generating NOX enzyme], NOXO2 [p47phox; organizer subunit of gp91phox]) associated with formation of NO, superoxide, PON, caspase1 p20, caspase-11 p20, NLRP3, and ASC, and vasodilator PGs (i.e., PGI2 and PGE2) [115–121,123–126,128,134] 4) promotion of formation/ activity of NLRP3/apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC)/procaspase-1 inflammasome [133]; and 5) increased formation of proinflammatory cytokines (i.e., TNF-α, IL-1β, and IL-8) and LTB4, malondialdehyde, and lactate dehydrogenase levels, myeloperoxidase and total antioxidant activity, expression/activity of caspase-3, superoxide dismutase, glutathione peroxidase, and glutathione reductase, and certain miRNAs (i.e., miR-150, miR-223, and miR-297) (Fig. 1) [118,119,121,123,124,126,130,134]. In these experiments, particularly N-(20-hydroxyeicosa-5[Z],14[Z]-dienoyl)glycine (5,14-HEDGE), which mimics the effects of endogenously produced 20-HETE, (30 mg/ kg; i.p.) prevented the LPS-induced vascular hyporeactivity, hypotension, and tachycardia in endotoxemic rats and LPS-induced mortality in mice [116,121,122,127,130,131,133]. Furthermore, 5,14-HEDGE increased renal, cardiac, and vascular expression of CYP2C23 and CYP4A1 PPARα/β/γ and RXRα in addition to the formation of EETs and 20-HETE in the LPS-treated rats. It also suppressed MyD88/TAK1/ IKKβ/κB-α/NF-κB and MyD88/TAK1/MEK1/ERK1/2/AP-1 pathways. Moreover, expression/activity of sEH, iNOS, sGC, PKG, COX-2, NOX2, NOXO2, importin-α3, caspase-1 p20, caspase-11 p20, NLRP3, and ASC were inhibited by 5,14-HEDGE. Decreased formation of proinflammatory cytokines (i.e., TNF-α, IL-1β, and IL-8), serum levels of miRNAs (i.e., miR-150, miR-223, and miR-297), neutrophil infiltration, and lipid peroxidation by 5,14-HEDGE was also observed. Additionally, it prevented the increase in both nuclear/cytosolic unphosphorylated and phosphorylated c-jun protein ratios in addition to importin-α3 protein as well as the decrease in nuclear/cytosolic PPARα/β/PPARγ protein ratios in the renal and cardiovascular tissues of endotoxemic rats. Moreover, a competitive antagonist of vasoconstrictor effects of 20-HETE, 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid, (30 mg/kg; i.p.) reversed the effects of 5,14-HEDGE on particularly vascular reactivity, MAP, and HR in addition to the expression/activity of CYP4A1, iNOS, PKG, COX-2, and NADPH in the rat model of septic shock. Overall, the results of the studies provide evidence that a stable analog of 20-HETE, 5,14-HEDGE: 1) down-regulates MyD88/TAK1/IKKβ/IκB-α/NF-κB and MyD88/TAK1/MEK1/ERK1/2/AP-1 pathways; 2) decreases NADPH oxidase activity and PON formation, expression/activity of transcription factors (i.e., NF-κB p65 and AP-1 subunit c-jun) and their translocation into the nucleus via importin-α3; 3) increases expression of PPARα/β/γ and RXRα and their nuclear translocation; 4) causes changes in the production of vasoactive mediators (i.e., NO, PGs, EETs, and 20-HETE) by certain enzymes (i.e., iNOS, COX-2, CYP2C23, and CYP4A1), and 5) inhibition of NLRP3/ASC/procaspase-1 inflammasome formation/activity, formation of proinflammatory mediators (i.e., TNF-α, IL-1β, and IL-8), and increased circulating levels of miR-150, miR-223, and miR-297 leading to vascular hyporeactivity, hypotension, tachycardia, inflammation, tissue injury, MOF, and mortality in the rodent model of septic shock.

Extensive in vivo studies have also demonstrated that the LPS-induced activation of innate immune response down- or up-regulates many CYP isoforms, particularly ω-hydroxylases and CYP epoxygenases, resulting in the alteration of eicosanoid content mainly in the renal, cardiac, vascular, hepatic, and respiratory tissues of animals [9,43,90,135–169]. For instance, De-Oliveira et al. [143] reported that LPS (E. coli LPS, O127:B8; i.p.) at doses > 2 mg/kg increases systemic levels of proinflammatory cytokines (TNF-α, IFN-γ, IL-6, and IL-17A) and NO associated with depressed hepatic CYP1A and -2B activities in mice. Blockade of proinflammatory cytokines and the overproduction of NO did not affect LPS-induced decrease in CYP1A and -2B expression. The results of the study of Anwar-Mohamed et al. [135] demonstrated that mRNA expression of CYP1A1 and -2 J3 was decreased in the kidney, heart, and liver of LPS (E. coli LPS, O127:B8, 1 mg/kg; i.p.)treated rats while CYP1A1 and -1B1 mRNA levels are increased by inflammation in the liver and heart. In the study, CYP2B1 mRNA level was also found to be decreased in the kidney and liver, but not in the heart of LPS-treated rats. With regard to CYP2C11 mRNA levels, CYP2C11 was inhibited in all tissues tested of LPS-treated rats. The gene expression of CYP4A1 was also increased in all tissues tested, and CYP4A3 was only increased in the heart of LPS-treated animals. These findings showed that the gene expression of CYP4F genes is altered by LPS treatment in a tissue-specific manner: 1) CYP4F1 mRNA level is increased in the heart at the early time point and decreased at later time points similar to what is observed in the kidney and liver of LPS-treated rats; 2) CYP4F4 mRNA level is significantly increased in the heart and decreased in the liver and kidney of LPS-treated rats; and 3) CYP4F5 mRNA level is similar to CYP4F1 in that its mRNA level is initially increased at early time point and then decreased at the later time points in the heart of LPS-treated rats while it decreased in the kidney, but not in the liver of LPS-treated rats. In the correlation studies regarding the effects of inflammation on CYP epoxygenases typified by CYP2B1, -2C11, and -2 J3 to EETs formation, it has been demonstrated that formation of all EET regioisomers with the exception of 14,15-EET is decreased in the heart microsomal fractions of LPS-treated rats. In addition, formation of the total heart EETs plus DHETs metabolites, as an index for the total epoxygenase activity, was decreased in response to LPS administration. The results of the study also showed that inflammation causes an increase in the production of 20-HETE in the heart microsomal fractions of the LPS-treated rats. In the study, the 20HETE:total EETs ratio, was also higher in the LPS-treated rats compared to control. The authors concluded that acute inflammation induced by LPS decreases CYP epoxygenases and their associated metabolites, EETs, while increases CYP ω-hydroxylases and their associated metabolites, 20-HETE. It should also be noted that the contradiction between the study and our findings with 5,14-HEDGE [116,121,122,127,130,131,133] could be attributed to differences in type and strain of animals, dose regimen, strain of LPS, and time points for measurement of enzyme expression and activity which might reflect the differences in the response to LPS treatment. LPS (E. coli LPS, O127:B8; 1 mg/kg; i.p.) treatment is also reported to suppress CYP4F4 and up-regulates CYP4F5 mRNA expression in rat liver whereas renal CYP4F1, -F5, and -F6 are essentially unchanged [144]. On the other hand, Sehgal et al. [158] demonstrated that mouse brain CYP4F4, -F13, -F14, -F15, -F16, and -F18) were expressed ubiquitously in several cell types in the brain, including neurons and microglia, and modulated inflammatory response triggered by LPS (E. coli LPS, O55:B5; 3 mg/kg; subcutaneusly) in vivo through metabolism of LTB4 to the inactive 20-hydroxy LTB4. Chemical inhibitor or short hairpin RNA to CYP4Fs enhance and inducer of CYP4Fs attenuated the inflammatory response. In addition, induction of CYP4F expression lowers LTB4 levels and affords neuroprotection in microglial cells or mice exposed to LPS. The authors suggest that catalytic activity of CYP4Fs is a novel target for modulating neuroinflammation through hydroxylation of LTB4. 8

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The results of the study by Warren et al. [164] demonstrated that 24 h after injection of LPS (E. coli LPS, 2 mg/kg; i.p.) to mice deficient in the p55 and p75 TNF receptors were decreased in hepatic CYP1A, -2B, and -4A expression independently of TNF-α. CYP2D9 activity also showed differential responses to LPS between wild-type and TNF p55/ p75 receptor knockout mice, indicating the down-regulation of CYP2D9 is differentially modulated by TNF-α expression. Barclay et al. [138] also demonstrated that renal expression of CYP4A10 and CYP4A14 was induced by LPS (E. coli LPS, O127:B8; 1 mg/kg; i.p.) treatment in wildtype (+/+) mice, and these effects were absent in the PPARα-null (−/−) mice. Hepatic expression of CYP4A10 was also down-regulated in the wild-type (+/+) animals, and no significant induction of CYP4A14 was detected in the liver. Furthermore, PPARα activation in the mouse kidney after LPS treatment was associated with down-regulation of CYP2A5, and CYP2C29. Since down-regulation of CYP2A5 and CYP2C29 by LPS was attenuated or blocked in the PPARα-null (-/-) mice, the authors suggested that PPARα has a role in CYP down-regulation. Moreover, Shimamoto et al. [159] demonstrated that the differential decrease in the hepatic contents of the total CYP (by 30% of the levels of control rats), CYP1A (48%), -2B (54%), and -2C11 (37%) in rats was observed 24 h after intracerebroventricular (i.c.v.) injection of LPS (E. coli LPS, O111:B4) at the dose ineffective (0.1 μg) when injected i.p.. Among CYPs examined, CYP2C11, was most severely affected by i.c.v. injection of LPS. The authors also reported that i.c.v. injection of LPS decreased the hepatic level of CYP2C11 mRNA (to 63% of saline i.c.v. control), the total P450 contents (to 70% of saline i.c.v. control), but not protein of CYP2C11 [159]. On the other hand, i.p. injection of LPS at the same dose as i.c.v. did not significantly affect these parameters. Therefore, the authors suggest that i.c.v. injection of LPS downregulates the expression of CYP2C11 at transcriptional level and the decrease in CYP2C11 mRNA may be involved in the decreased level of protein and activity of CYP2C11 by i.c.v. injection of LPS in rat liver. It has also been suggested that the sympathetic nervous systems both directly and indirectly innervating the liver do not participate in the primary mechanism of the decrease in the activities of CYP isozymes in rat liver microsomes induced by i.c.v. administration of LPS. In addition, the adrenal glands, especially the adrenocortical system, may play a suppressive role in the decrease in CYP isoforms caused by i.c.v. injection of LPS [161]. It has been shown that compared to wild-type controls, CYP2 J2 transgenic, CYP2C8 transgenic, and Ephx2-/- mice each exhibits a significant attenuation of LPS (E. coli LPS, O111:B4; 40 mg/kg; i.p.)-induced activation of NF-κB signaling, cellular adhesion molecule, chemokine and cytokine expression, and neutrophil infiltration in lung in vivo [141]. The results of the study suggest that potentiation of the CYP epoxygenase pathway attenuates acute, NF-κB-dependent vascular inflammatory responses in vivo, and may serve as a viable anti-inflammatory therapeutic strategy. Dong et al. [142] also demonstrated that increased levels of EETs by endothelial specific CYP epoxygenase, CYP2 J2, overexpression in the lung of LPS (15 mg/kg; i.p.)-treated mice. sEH inhibition also caused a reduction in LPS-induced endothelial hyperpermeability in vivo associated with improved survival of septic mice. Therefore, the authors concluded that CYP2 J2/EETs may be a potential target for lung hyperpermeability induced by LPS treatment, which may contribute to the development of new therapeutic approaches for pulmonary edema and other diseases caused by abnormal vascular permeability. On the other hand, the findings of Fife et al. [144] suggest that there is no reduction in the LPS (E. coli LPS, O55:B5; 1 mg/kg; i.p.)-induced hepatic inflammatory response following continuous chemical inhibition or genetic disruption of sEH in mice, even though EET/DHET ratios indicated robust sEH inhibition. Furthermore, the results of the study by Zhou et al. [168] demonstrated that inhibition of sEH attenuated the morphological changes in addition to the decreased formation of 14,15-EETs associated with increased levels of proinflammatory cytokines (IL-1β and TNF-α) in serum and/or

bronchoalveolar lavage fluid in mice treated with LPS (E. coli LPS, O111:B4; 5 mg/kg; i.p.). sEH inhibition also improved the survival rate of LPS-induced acute lung injury (ALI). The authors suggest that EETs play a role in dampening LPS-induced acute lung inflammation and sEH could be a valuable candidate for treatment of ALI. As demonstrated by Theken et al. [163], hepatic CYP2C29, -2C44, and -2 J5 mRNA levels and EET + DHET formation are decreased 24 and 48 h after LPS (E. coli LPS, O111:B4; 1 mg/kg; i.p.) administration. In the study, hepatic CYP4A12a, -4A12b, and −4 F13 mRNA levels and 20-HETE formation was found to be lower at 24 h, but recovered to baseline at 48 h, resulting in a significantly higher 20-HETE/ EET + DHET formation rate ratio compared with that for control mice. Renal CYP mRNA levels and CYP-mediated eicosanoid metabolism were similarly suppressed 24 h after LPS treatment. Pulmonary EET + DHET formation was lower at all time points after LPS administration while 20-HETE formation was suppressed in a time-dependent manner, with the lowest formation rate observed at 24 h. No differences in EET + DHET or 20-HETE formation were observed in heart. The authors concluded that acute activation of the innate immune response alters CYP expression and eicosanoid metabolism in mice in an isoform-, tissue-, and time-dependent manner. 4.2. Eicosanoids derived from CYP pathway of AA in zymosan-induced inflammatory shock Another rodent model of toxin administration is the peritoneal injection of nonbacterial and nonendotoxic agents like zymosan [11,100]. Zymosan, a stimulatory cell wall extract of the yeast Saccharomyces cerevisiae, can elicit a septic shock like syndrome in rodents in the absence of endotoxin. It induces a robust inflammatory response through a wide range of proinflammatory mediators and concomitant MOF when injected to animals. Unlike LPS or other TLR agonists, the host response to zymosan is trimodal. There is an early proinflammatory response lasting several days that induces dose-dependent mortality. This is followed by a quiescent period of chronic low-grade inflammation that progresses to a final stage characterized by organ failure and death. Depending on the dose employed, the mortality in the early and late inflammatory periods can be titrated. The model offers the advantage of a semblance of human sepsis where the sepsis event is prolonged and MOF is both an early and late phenomenon. Closer examination suggests that this is a model of an early exaggerated inflammatory response with persistent inflammation, ultimately leading to organ injury. In one of the limited number of studies, it has been reported that the 90% reduction in tissue CYP content achieved by nonspecific CYP inhibitor, 1-aminobenzotriazole, is associated with 58% mortality in rats treated with low dose zymosan, the cell wall of Saccharomycoses A, (200 mg/kg), in contrast to no mortality in rats treated with the dose zymosan alone [170]. In survivors, liver and lung organomegaly, and polymorphonuclear leukocyte accumulation in the liver were increased after zymosan administration in rats treated with 1-aminobenzotriazole compared to those without 1-aminobenzotriazole. The authors suggest that the CYP enzyme system is an endogenous protectant in this experimental model of inflammation-induced MOF. In addition, hepatic expression of CYP2 J5, 2 J6, -2C9, -2C38, -2C44, -2C50, -2C54, and -2C55 mRNA was observed in mice treated with zymosan A (1 mg/kg; i.p.) for 24 h. During the acute inflammatory response elicited by zymosan (4 h), increased levels of 5-, 11-, 19-, and 20-HETE, the CYP epoxygenase-derived oxylipins, 5,6-, 8,9-, 11,12-, and 14,15-DHET, and 17,18-dihydroxy-eicosatetraenoic acids were also detected in the peritoneal cavity lavage fluid of mice [171]. It has also been reported that 5-, 8-, and, 15-HETE, 5,6-, and 11,12-EET levels are increased in the peritoneal cavity of mice treated with zymosan A (1 mg/mouse; i.p.) for 4 h [172]. The findings of the studies suggest that eicosanoids produced by ω-hydroxylase and CYP epoxygenase pathways are involved in the zymosan-induced inflammatory shock. 9

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4.3. Eicosanoids derived from CYP pathway of AA in models of inflammatory shock with exogenous administration of a viable pathogen

HeJ) mice was similar to that in HeOu mice for most CYPs, with the exception of the TLR4 dependence of CYP4F15. Hepatic CYP2C, -3A, and -4A proteins in both groups were decreased, whereas CYP2E protein was not. Renal CYP4A10 and -4A14 mRNAs were significantly down-regulated in HeOu mice, whereas other CYPs were unaffected. Most renal CYP mRNAs in infected HeJ mice were increased, notably CYP4A10, -4A14, −4 F18, -2A5, and -3A13. Hepatic levels IL-1β, IL-6, and TNF-α) mRNAs were also significantly increased in infected HeOu mice, whereas only TNF-α mRNA was significantly increased in HeJ mice. These authors suggest that hepatic inflammation induced by C. rodentium infection is mainly TLR4-independent and suggest that hepatic CYP down-regulation in this model may be cytokine-mediated. Different patterns of CYP expression were also observed when comparing intestinal and systemic infections of C. rodentium. For instance, as in HeOu mice, CYP4A mRNAs and proteins were among the most sensitive to down-regulation, whereas CYP4F18 and CYP2D9 mRNAs were induced in the C57BL/6 mice [186]. The time course of CYP regulation followed that of colonic inflammation and bacterial colonization, peaking at 7 to 10 days after infection and returning to normal at 15 to 24 days as the infection resolved. These changes were also correlated with the time course of significant elevations in the serum of the proinflammatory cytokines IL-6 and TNF-α, as well as of IFN-γ and IL-2, with serum levels of IL-6 being markedly higher than those of the other cytokines. In addition, administration of C. rodentium (i.p.) produced a rapid down-regulation of CYP enzymes that was quantitatively and qualitatively different from that of oral infection, although CYP2D9 was induced in both models, suggesting that the effects of oral infection on the liver are not due to bacterial translocation. Nyagode et al. [187] also reported that the majority of CYP mRNAs were equally affected by C. rodentium infection in each genotype, indicating that IL-6 and IFN-γ are not the primary mediators of CYP down-regulation in this disease model. The down-regulation of CYP3A11 and -3A13 and induction of CYP2D9 mRNAs were attenuated in the IL-6 (-/-) mice, suggesting a role of IL-6 in the regulation of only these CYPs. Similar evidence implicated IFN-γ in the regulation of CYP2D9, -2D22, -3A11, -3A25, and −4 F18 mRNAs in C. rodentium infection and CYP2B9, -2D22, and -2E1 in the bacterial LPS model of inflammation. In addition, Kinloch et al. [188] demonstrated that CYP4A mRNA and protein levels were down-regulated, while CYP2D9 and −4 F18 mRNAs remained elevated during C. rodentium infection in wild-type in addition to TNF-α receptor 1 null mice (TNFR1 [-/-]) and IL-1 receptor null mice (IL1R1 [-/-]) knock-out mice. CYP3A11 and -3A25 mRNA levels were down-regulated during infection in wild-type mice but not in TNFR1 (-/-) mice. Consistent with this observation, CYP3A11 and -3A25 were potently down-regulated in mouse hepatocytes treated with TNF-α. Oral infection of IL-1R1 (-/-) mice and studies with mouse hepatocytes indicated that IL-1 does not directly regulate CYP3A11 or CYP3A25 expression. The authors conclude that TNF-α is involved in the regulation of CYP3A11 and -3A25, but IL-1β may not be relevant to hepatic CYP regulation in oral C. rodentium infection.

Administration of live bacteria (such as E. coli, Pseudomonas aeruginosa [P. aeruginosa], Staphylococcus aureus [Staph. aureus], or Citrobacter rodentium [C. rodentium]) to many species through multiple routes replicates many of the characteristics seen in clinical sepsis [173–176]. Administration of bacteria cultured in vitro at predefined doses of colony forming units can cause reproducible clinical alterations and mortality [173,177]. In addition, this model can allow researchers to target particular types of sepsis (i.e., Gram-negative vs Gram-positive) [101]. A rat model of sepsis was also produced by introducing pure bacterial cultures into the peritoneal cavity [178,179]. On the other hand, it has been suggested that this type of procedure is unable to result in significant mortalities [180]. Although these bacterial infection models do not resemble many important characteristics of clinical sepsis, they can reproduce several features of septic shock and contribute significantly to the understanding of host defense mechanism against infection. These models can also be used to observe the blood clearance kinetics of bacteria. In addition, a massive bacteria load is used to overwhelm host defense and induce sepsis. However, large amount of bacteria commonly administered do not typically colonized and replicate within the host because of rapid lysis by complement. Immunological response may also vary depending on bacterial strain. Thus, the transient introduction of high doses of bacteria into an animal may be a potential model of intoxication with endotoxins rather than a model of sepsis. It seems to be more appropriate to choose an experimental host capable of being efficiently infected at relatively low doses with an appropriate pathogen of which the initial colonization progresses to sepsis [3,47,100,101]. Another model is the inoculation of bacterial fibrins capable of activating the innate immune system. However, intraabdominal sepsis has been less frequently induced through implantation of a fibrin clot impregnated with pathogen [66,100]. This creates a persistent nidus of infection with progression to systemic dissemination, modeling human sepsis [181]. The benefit of introducing bacteria into the fibrin clot is that the fibrin delays systemic absorption of the entrapped bacteria, which promotes development of a local septic focus. In addition, this method reduces early mortality and the researcher is able to select for the particular strain of bacteria to be introduced into the murine host [174]. This limitation of this model is the use of a single organism culture, which differs from the polymicrobial infection seen in intraabdominal sepsis in humans [99]. Finally, cecal slurry is another commonly used to induce polymicrobial sepsis [181–184]. This method involves i.p. injection of a measurable amount of cecal contents from a donor mouse into a recipient mouse. Although this model is preferable in neonatal mice given their small size and the technical ease to perform cecal slurry, inflammation does not persist as long as CLP or CASP in this model [66,100]. To the best of our knowledge, there has been no previous attempt to examine the involvement of eicosanoids derived from CYP pathway of AA in models of inflammatory shock with implantation of fibrin clot impregnated with viable bacteria and cecal slurry injection. On the other hand, there are limited animal studies regarding the involvement of eicosanoids derived from CYP pathway of AA in models of inflammatory shock with exogenous administration of a live bacteria [185–188]. Richardson et al. [185] demonstrated that a mouse model of live bacterial infection with C. rodentium, a Gram-negative pathogen, caused a different pattern of hepatic CYP mRNA expression compared to sterile inflammation induced by LPS. For instance, hepatic CYP4A10 and -4A14 mRNAs were decreased in wild-type (C3H/HeOuJ; HeOu) mice (< 4% of control). CYP3A11, -2C29, −4 F14, and −4 F15 mRNAs were reduced to 16–55% of control levels, whereas CYP2A5, −4 F16, and −4 F18 mRNAs were induced (180, 190, and 600% of control, respectively). The pattern of CYP regulation in TLR4 mutant (C3H/HeJ;

4.4. Eicosanoids derived from CYP pathway of AA in CLP- and CASPinduced inflammatory shock Several studies demonstrate that the CLP model of polymicrobial sepsis produces a resulting immune, hemodynamic, and biochemical response in the murine host that is similar in many regards to the septic response seen in humans. Furthermore, similar immunological, metabolic, and apoptotic responses are observed in the CLP model as in human disease, strengthening the validity of this model. Therefore, CLP is a widely used and carefully characterized model of infection that responds to fluid resuscitation and antibiotics [11,98–100]. This model is characterized by increased cardiac output and organ blood flow in early stage (i.e., hyperdynamic phase, 6 h after onset of sepsis) and decreased tissue perfusion at the late stage (hypodynamic phase 18 h 10

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after onset of sepsis). In this model, sepsis develops due to peritoneal contamination with mixed flora (anaerobic to facultatively to aerobic, Gram-positive and Gram-negative microorganisms) in the presence of devitalized or ischemic/necrotic tissue and, thus, bears a distinct resemblance to clinical reality. The procedures in this model include midline laparotomy, exteriorization of the cecum, ligation of the cecum distal to the ileocecal valve and puncture of the ligated cecum. This surgical operation produces a bowel perforation with leakage of feces into the peritoneum and, thus, causes peritoneal contamination with mixed flora in devitalized tissue. The severity of sepsis, as evaluated by mortality rate, is related to the needle puncture size or the number of punctures. One problem that can arise with CLP-induced sepsis is the formation of a walled-off abscess, thus producing more of an intraabdominal abscess model than a true sepsis model. One proposed solution to this concern has been the introduction of the CASP model of acute polymicrobial septic peritonitis [11,66,96,99–101]. In CASP, a stent is inserted into the colon ascendens of the rodent, this leads to persistent leakage of fecal material into the peritoneal cavity, causing a polymicrobial sepsis and peritonitis. The procedure involves a laparotomy, insertion and fixation of the stent, and fluid resuscitation. CASP is associated with bacteremia and elevated circulating endotoxin levels. Bacteremia is detected as early as 12 h post-stent implantation and increased serum LPS is seen as early as 2 h post-stent implantation. CASP produces a robust inflammatory response similar to that seen in clinical human sepsis. CASP mortality is also associated with MOF. A direct comparison between the CLP and CASP models has shown stronger induction of cytokines and higher bacterial counts in blood with the CASP model. It has been proposed that this occurs because CASP produces a more consistent diffuse peritonitis with persistent systemic inflammation, as opposed to CLP, which can lead to a walled-off abscess with less systemic inflammation. While this model is appealing, CASP is technically more challenging to perform than CLP, which has limited its application. As far as we know, there has been no previous attempt to examine the involvement of eicosanoids derived from CYP pathway of AA in models of CASP-induced inflammatory shock. However, the results of several in vivo studies demonstrate that expression and/or activity of ωhydroxylases and CYP epoxygenases in the respiratory and hepatic tissues of animals are changed in the CLP model [156,189–197]. For instance, the results of the study by Cui et al. [189] indicated that the gene expression of CYP2C11 and CYP2 J4 in the lungs of mice was significantly down-regulated at 20 h after CLP, whereas the expression of CYP4A3 was markedly up-regulated at 5 h. The protein concentrations of CYP2C11 were also decreased at 20 h after CLP. Although total peripheral resistance markedly increased, MAP did not change at 20 h after the onset of sepsis. On the other hand, cardiac output and pulmonary perfusion decreased in late sepsis. The authors suggest that since the up-regulated CYP4A3 is associated with the early, hyperdynamic phase of sepsis and the down-regulated CYP2C11 and CYP2 J4 are associated with the late, hypodynamic phase, vascular CYP isoforms that metabolize AA may be involved in regulating the cardiovascular response during the progression of sepsis. Hepatic microsomal CYP content in addition to the activity of CYP1A1 and -1A2, but not CYP2B1, was also found to be reduced in CLP rats [190]. The amount of the CYP1A1 and -1A2 proteins in the microsomes associated with CYP1A1, -1A2, and -2B1 mRNA levels was decreased after CLP and inhibition of NO synthesis reversed these effects of LPS. The results of the study suggest that NO plays a key role in the sepsis-mediated decrease in CYP via the interplay of two different mechanisms: 1) NO-dependent suppression of protein via the enhanced iNOS and 2) NO-dependent transcriptional suppression via eNOS. On the other hand, it has been demonstrated that total hepatic CYP content in addition to CYP1A1 activity and its protein level is decreased 24 h after CLP while CYP1A2 activity is decreased 2 h and 24 h after CLP [194]. Although CYP2B1 mRNA expression level was decreased 6 h and

24 h after CLP, CYP2B1 activity and its protein level did not change in any of the experimental groups. TNF-α mRNA and iNOS mRNA expression levels were also increased 2, 6, and 24, and 24 h after CLP. The authors concluded that the individual CYP isoforms appear to be differentially affected by septic injury and the production of NO, ROS, and TNF-α during sepsis may damage these CYP isoforms. In a "double-hit" model of hemorrhage and sepsis, it has been shown that hepatic expression of CYP1A2 and -2C11 as well as PPAR-γ are down-regulated after the initial stress (hemorrhage). On the other hand, double-hit (CLP) did not appear to further decrease CYP and PPAR-γ gene expression. Therefore, it has been suggested that the down-regulated CYPs and PPAR-γ seem to work as important factors contributing to the progression of organ injury and proinflammatory responses after the second stress (CLP) [191]. 5. Summary and perspectives The current management of patients with septic shock relies on immediate treatment with antibiotics and high-quality supportive care to control hypotension and tissue oxygenation to maintain organ function. However, the failure of conventional therapy is that the physiopathology of septic shock is the result of a highly complex set of processes in which the host response becomes dysregulated and causes tissue damage and ultimately organ failure. Despite the disappointment of many translation observations from animal models to the clinical setting, animal models of inflammatory shock will continue to play an essential role in identifying new inflammatory mediators and testing of new potential drug candidates. A better understanding of how to apply different animal models in different conditions may help us beware of pitfalls. Among the critical inflammatory mediators identified in animal models of inflammatory shock, some have shown promising clinical relevance. Accumulating evidence from preclinical studies suggest that the contribution of 20-HETE and EETs generated via CYP ω-hydroxylases and CYP epoxygenases, respectively, to diseases associated with inflammation such as sepsis and septic shock is beginning to emerge. Polypharmacology is nowadays considered an increasingly crucial aspect in drug discovery over the last two decades as several original single-target drugs have been performing far behind expectations. In this scenario, multitarget drugs are a promising approach against polygenic diseases with complex pathological conditions. Therefore, dual inhibitors/modulators targeting the CYP ω-hydroxylases and CYP epoxygenases or 20-HETE and EET agonists/antagonists may have a high potential as an effective and safe strategy for diseases associated with inflammation. However, in light of the critical role of eicosanoids derived from CYP pathway of AA in addition to NO in hypotension, inflammation, MODS, MOF, and mortality due to sepsis, the interaction of CYPs, particularly with NOS, COX, NF-κB, and MAPK pathways [19,20] should also be considered when developing new strategies for drug development in the treatment of septic shock. With the increase of our knowledge about the pathogenesis of inflammatory shock and the development of specific mimetics or inhibitors of eicosanoids derived from CYP pathway of AA, new clinically effective therapeutics may be discovered in the future studies to prevent hypotension and inflammation which lead to MOF and death due to septic shock in the ICU. Declaration of Competing Interest The authors declare that they have no competing of interests. Acknowledgments This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Our studies presented in this review were supported in part by grants from Mersin University (BAP ECZ F EMB [KB] 2003-1, BAP ECZF EMB [BT] 2004-3, 11

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BAP ECZF EMB [BT] 2006-3, BAP SBE EMB [RBK] 2006-3 DR, BAP SBE EMB [TC] 2008-6 DR, BAP-ECZ F FB [BT] 2010-5 B, BAP SBE F [MK] 2011-5 YL, BAP-SBE EMBB [ANS] 2012-4 DR, BAP-ECZ F EMBF [SŞF] 2012-6 B, BAP-SBE FB [SPS] 2014-3 YL, and 2015-AP3-1343), Novartis Turkey, TUBITAK (SBAG-106S299, SBAG-109S121, and SBAG215S679), USPHS NIH (R01HL139793), and the Robert A. Welch Foundation (I-0011).

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