- Email: [email protected]
Matrix metalloproteinases in pneumonia
Clinica Chimica Acta 433 (2014) 272–277
Contents lists available at ScienceDirect
Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Invited critical review
Matrix metalloproteinases in pneumonia☆ Ting-Yen Chiang a, Shih-Ming Tsao a,b, Chao-Bin Yeh a,c, Shun-Fa Yang d,e,⁎ a
School of Medicine, Chung Shan Medical University, Taichung, Taiwan Division of Infectious Diseases, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan c Department of Emergency Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan d Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan e Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan b
a r t i c l e
i n f o
Article history: Received 19 January 2014 Received in revised form 25 March 2014 Accepted 26 March 2014 Available online 8 April 2014 Keywords: Pneumonia Matrix metalloproteinase
a b s t r a c t Pneumonia is a worldwide infectious disease that is associated with significant morbidity and mortality and is the most common fatal infection acquired in hospitals. Despite advances in preventive strategies, such as antibiotic therapies and intensive care, the mortality rate still requires substantial improvement. Matrix metalloproteinases (MMPs) are a large family of zinc-dependent endopeptidases, which are known as the major enzymes responsible for the proteolytic degradation of proteinaceous components of the extracellular matrix (ECM). Although the main function of MMPs is the removal of the ECM during tissue resorption and progression of various diseases, MMPs also interact with multiple cytokines, participating in the pathology of infection and inflammation. This review presents a schematic overview of the different MMPs expressed in pneumonia. MMPs are key factors in the pathogenesis of various types of pneumonia, such as community-acquired pneumonia, hospital-acquired pneumonia, and ventilator-associated pneumonia. Here, we review the pathological roles of various MMPs in pneumonia. © 2014 Elsevier B.V. All rights reserved.
Contents 1. 2. 3.
Introduction to pneumonia . . . . . . . . . . . . . Three types of pneumonia . . . . . . . . . . . . . . Matrix metalloproteinases participating in the pathology of inflammation . . . . . . . . . . . . . . . . . . 4. Role of matrix metalloproteinases in pneumonia . . . . References . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
272 272
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
273 274 275
1. Introduction to pneumonia Pneumonia is associated with significant morbidity and mortality, causing the deaths of 3.2 million people in 2011 and ranking third among the 10 most common causes of death worldwide [1]. The primary method for diagnosing pneumonia is the identification of a microbiological pathogen isolated directly from lung tissue; however, this invasive procedure is not routinely performed. Performing clinical evaluations followed by chest radiography can help physicians to preliminarily ☆ The authors have declared no conflicts of interest. ⁎ Corresponding author at: Institute of Medicine, Chung Shan Medical University, 110, Section 1, Chien-Kuo N. Road, Taichung, Taiwan. Tel.: +886 4 24739595x34253; fax: +886 4 24723229. E-mail address: [email protected] (S.-F. Yang).
http://dx.doi.org/10.1016/j.cca.2014.03.031 0009-8981/© 2014 Elsevier B.V. All rights reserved.
determine pneumonia impressions [2], and laboratory techniques, such as Gram's stain, sputum cultures, blood cultures, antigen tests, polymerase chain reaction, and serology, can be used to determine the potential etiology [3]. Biological markers are occasionally used to evaluate pneumonia [4]. Thus, developing a biomarker for performing rapid and reliable diagnoses would be beneficial.
2. Three types of pneumonia Pneumonia is defined as an infection of the pulmonary parenchyma that develops from the proliferation of microbial pathogens at the alveolar level of the respiratory track and the response of the host itself [5]. Because the epidemiology, pathogenesis, and risk factors for infection of pneumonia patients are different, the American Thoracic Society
T.-Y. Chiang et al. / Clinica Chimica Acta 433 (2014) 272–277
and Infectious Diseases Society of America have developed guidelines for distinguishing among three types of pneumonia. Communityacquired pneumonia (CAP) is defined as pneumonia acquired from the community. Hospital-acquired (or nosocomial) pneumonia (HAP) is defined as pneumonia that occurs 48 h or more after hospital admission and does not appear to be incubating at the time of admission. Among HAP patients, those who develop pneumonia after more than 48 to 72 h of endotracheal intubation are classified as having ventilatorassociated pneumonia (VAP) [6,7]. The etiology of pneumonia includes bacteria, viruses, fungi, and protozoa [8]. Generally, two groups of pathogens that potentially cause pneumonia exist: “typical” bacteria, including Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and gram-negative bacilli, such as Klebsiella pneumoniae and Pseudomonas aeruginosa; and “atypical” organisms, including Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella species, and respiratory viruses, such as influenza viruses, adenoviruses, and respiratory syncytial viruses. Determining whether a case is typical or atypical pneumonia is imperative because this diagnosis provides considerable implications for therapy. However, 11–20% of pneumonia cases are polymicrobial, and the etiology often includes a combination of typical and atypical pathogens [9]. 3. Matrix metalloproteinases participating in the pathology of inflammation Matrix metalloproteinases (MMPs), which are also called matrixins, are a large family of zinc-dependent endopeptidases that are known Table 1 Classification of MMPs.
273
as the major enzymes responsible for the proteolytic degradation of proteinaceous components of the extracellular matrix (ECM) [10], which are essential for embryonic development, morphogenesis, reproduction, tissue homeostasis, tumorigenesis, and organ fibrogenesis [11, 12]. Excreted MMPs contain 23 proteases in humans and are categorized into four classes based on their substrate specificity (Table 1): collagenases (MMP-1, -8, and -13); gelatinases (MMP-2 and -9); stromelysins (MMP-3, -10, and -11); and a heterogeneous group that includes matrilysin (MMP-7), metalloelastase (MMP-12), enamelysin (MMP-20), endometase (MMP-26), and epilysin (MMP-28). The membrane MMPs (MMP-14, -15, -16, -17, -24, and -25) are anchored to the cell surface. An alternate classification system that categorizes the MMPs based on domain structure is also used [13]. MMPs typically consist of four domains: the propeptide domain, which contains a cysteine-switch motif for ligating catalytic zinc to maintain the latency of the inactive form of MMPs [14]; the catalytic domain, which contains two zinc ions that coordinate with the zincbinding motif HEXXHXXGXXH and a conserved methionine, which forms a unique Met-turn structure for stabilization [15]; and the cysteine residue in the propeptide domain interacts with the catalytic zinc ion, which prevents its association with water molecules until the propeptide domain is removed [16]. Except for MMP-7, MMP-23, and MMP-26, MMPs have C-terminal hemopexin-like domains that are recognized by substrates. The hemopexin domain consists of a four-bladed propeller structure and confers substrate specificity to the MMPs; thus, degradation of the triple-helical collagens is absolutely necessary [17].
274
T.-Y. Chiang et al. / Clinica Chimica Acta 433 (2014) 272–277
Each type of MMP contains a linker region that varies in length, and several MMPs possess slight structural differences. The gelatinases (MMP-2 and -9) contain three repeats of a fibronectin type II inserted into the catalytic domain for binding to gelatin and collagen [18]. MMP-23 contains a cysteine-rich region and an immunoglobulin domain instead of the hemopexin domain [19]. Finally, membrane-type MMPs contain a transmembrane domain or a glycosylphosphatidylinositol anchor [16, 20]. MMP function is regulated at several levels. The first level of control of MMP production is transcriptional regulation. The induction of gene expression is controlled by effectors, including growth factors, cytokines, chemical agents, physiological stress, and oncogenic cellular transformation. In addition, enhanced MMP gene expression may be downregulated by suppressive factors, such as transforming growth factor b, retinoic acids, or glucocorticoids. Moreover, specific signaling pathways result in the expression of particular MMP genes [11]. For example, activation of the Rho family guanosine triphosphatase (GTPase) pathway increased the expression of MMP-1 [21]; ultraviolet B (UVB) irradiation mediated signaling pathway up-regulates MMP-1 and MMP-3 expression [22]. Moreover, activation of the ceramide signaling pathway inhibits MMP-1 gene expression [23]. Most MMPs are translated into an inactive zymogen form. Secreted zymogens are activated either intracellularly by zymogen convertases, such as furin, in the normal secretory pathway, at the cell surface, or extracellularly by other proteases [16]. In all cases, activation requires the disruption of the Cys–Zn2+ (cysteine switch) interaction [24]. For example, in neutrophils, specific MMPs (MMP-8 or MMP-9) can be stored as proenzymes in intracellular granules, and their exocytosis is stimulated by external signals (including cytokine signaling or CD40 signaling) [16]. Finally, active MMP proteins are naturally inhibited by tissue inhibitors of metalloproteinases (TIMPs) in extracellular environments [16]. Although the main function of MMPs is the removal of the ECM during tissue resorption and the progression of various diseases, MMPs also interact with numerous cytokines, participating in the pathology of infection and inflammation [11,25]. In the pathology of pneumonia, an infectious disease, MMPs are understandable and have been shown to play a role.
4. Role of matrix metalloproteinases in pneumonia The first line of defense against invasive respiratory pathogens is the airway epithelium, and the mechanisms include the prevention of bacterial colonization and infection in the airways. Epithelial cells maintain a barrier to the environment, and provide enzymes (such as lysozyme, β-defensins, cathelicidin, and other enzymes [26]) and an airway mucus layer for physical protection [27]. In addition, they regulate inflammation as a secondary line of defense in response to infection by secreting factors that recruit inflammatory cells to attack invasive pathogens; MMPs are components of these factors [28], and several reports have described the presence of an increased epithelial MMP
expression in response to bacterial infection, such as those of MMP-7 [29], MMP-10 [28], and MMP-28 [30] (Table 2). MMP-7 and MMP-28 are constitutively expressed in low concentrations by bronchial epithelial cells and are induced by bacterial infections [30–32]. Previous studies have reported that MMP-7 has several functions involved in immune responses, which include re-epithelializing airways by cleaving E-cadherin [33,34], processing antibacterial peptides [35], regulating acute alveolar neutrophil transepithelial migration by shedding syndecan-1/KC complexes [31], clearing pathogens [36] by promoting apoptosis through the generation of soluble Fas (CD95) ligands [36,37], and regulating growth factor signaling through epidermal growth factors and insulin-like growth factors [38]. MMP-28 has been shown to control neutrophil recruitment into the lung in a P. aeruginosa pneumonia model [30]. Most MMPs play roles in maintaining immunity by cleaving specific proteins, which increases the activity of the target substrates [39]. For example, MMP-2, MMP-3, and MMP-9 can activate IL-1β [40], and MMP-7 and MMP-12 can activate latent TNFα [41–43]. In addition, MMP-28 restrains macrophage recruitment by retarding the chemotaxis of these cells [30]. Moreover, Kassim et al. demonstrated that MMP-10 restrains the inflammatory response and controls apoptosis [28]. In the lung, neutrophils are located in the vascular bed. Neutrophils are recruited to pulmonary capillaries by inflammatory cytokines, such as interleukin-8 (IL-8) and leukrotrien B4 in patients with pneumonia [44]. Subsequently, the activated MMPs contribute to neutrophil migration into the alveolar compartment [45]. The release of MMP-8 and MMP-9 [44,46] is speculated to result in a disruption of basement membrane components, which facilitates the neutrophil invasion of extravascular tissue [47]. However, Rosendahl et al. proposed that bacteria can exploit MMP-9 to open tissue barriers and cause its own dissemination from the local site of infection using an S. pneumonia-infected model [48]. In the role of degrading the tissue barriers, MMPs have two aspects in the pathology of pneumonia, it benefits the inflammatory cells to infiltrate to the infected site; simultaneously, it results in the dissemination of the pathogen. The alveolar compartment is the location where neutrophils degranulate with the exocytosis of MMPs, such as MMP-8, MMP-9 [49], as well as other types of neutrophil granules and reactive oxygen species, which can execute antimicrobial functions [50]. In pneumonia patients, compared with peripheral neutrophils, pulmonary neutrophils are highly stimulated during infections to release MMPs [51]. Released MMPs are activated by bacterial MMPs [52], plasmin [53], or other neutrophil products such as myeloperoxidase and neutrophil elastase [44,54]. Oggioni et al. discovered that a pneumococcal zinc metalloproteinase can cleave and activate MMP-9 in a murine model of pneumonia [44]. MMP-9 and MMP-2 play key roles in the migration of various leukocytes, such as T cells and neutrophils [47]. MMP-2 and, to a lesser degree, MMP-9 were observed to efficiently cleave and inactivate IL-17A, which is a pathogen-associated proinflammatory molecule that induces the recruitment of activated neutrophils to infection sites [55].
Table 2 Role of MMPs in pneumonia. MMPs
Pneumonia
MMP-2, MMP-9 MMP-2, MMP-9 MMP-7 MMP-7, MMP-10 MMP-8, MMP-9 MMP-8, MMP-9 MMP-8, MMP-9 MMP-8, MMP-9, TIMP-1 MMP-9 MMP-9, TIMP-1 MMP-9, LCN2 MMP-28
S. pneumoniae pneumonia in murine model M. pneumoniae CAP Airway epithelial cells infected with P. aeruginosa in vivo P. aeruginosa pneumonia in murine model HAP HAP with high-risk bacteria VAP P. aeruginosa VAP CAP CAP CAP P. aeruginosa pneumonia in murine model
References MMPs serves in the early host immune response MMP-9 activity elevated in M. pneumoniae CAP patients Infection induced MMP-7 expression Infection induced MMP expression MMP levels are increased in HAP patients MMP activities are elevated in HAP patients MMPs elevated in VAP patients Higher MMP-9/TIMP-1 ratio determine poor outcome MMP-9 elevated in CAP patients MMP-9/TIMP-1 ratio elevated in CAP patients LCN2/MMP-9 correlated with the CAP severity MMP-28 negative regulates macrophage recruitment
Hong et al. [57] Puljiz et al. [77] Lopez-Boado et al. [29] Kassim et al. [28] Hartog et al. [51] Schaaf et al. [44] Wilkinson et al. [68] El-Solh et al. [61] Yang et al. [69] Chiang et al. [72] Yeh et al. [75] Manicone et al. [30]
T.-Y. Chiang et al. / Clinica Chimica Acta 433 (2014) 272–277
High levels of MMP-9 in the lungs were reported to promote the infiltration of inflammatory cells [56]. Furthermore, MMP-9 is critical for effective bacterial phagocytosis and the generation of reactive oxygen species in neutrophils [57]. In addition, MMP-2 and MMP-9 have been reported to play roles in regulating adaptive immune processes by degrading ECM proteins and modifying chemokines [57]. Hong et al. elaborated that MMP-2 and MMP-9 serve as anti-inflammatory mediators by avoiding excess neutrophil recruitment to the lung, and MMP-9 is essential to neutrophil-mediated bacterial killing as well as phagocytosis. Thus, the mortality rate increased in S. pneumoniae-infected MMP-2, 9−/− mice [57]. MMPs were reported to contribute to the innate immune and adaptive immune systems. Furthermore, they were shown to be crucial factors in eliminating pathogen and protecting the host itself from its own immune system. A positive feedback loop exists between cytokines and MMPs. For example, MMP-9 cleaves IL-8 into an active form, which increases MMP-9 levels, resulting in a potent IL-8 [49]. This type of positive feedback may maintain excessive MMP activity, such as the degradation of ECM, which eventually leads to severe ECM destruction and alveolocapillary leakage accompanied by an increased risk of developing acute respiratory distress syndrome (ARDS), which is the most severe complication of pneumonia [49]. The local production of MMPs can directly alter the local tissue architecture by degrading proteins of the ECM [58]. The evidence suggests that MMPs in the lung control the pathogenesis of ARDS by disrupting structures of the basement membrane. Torii et al. reported that in ARDS patients, MMP-9 levels were correlated with 7S collagen, a marker of basement membrane disruption [59]. In such cases, inhibition of MMP activity may attenuate several crucial pathogenetic steps in the inflammatory cascade, such as preventing an acute lung injury from severe infection [60]. In the pathology of pneumonia, MMPs might have a dual effect involving the ultimate outcome, duration of exposure, site of release, and characteristics of the defending pathogen [61]. HAP is the leading cause of death among hospital-acquired infections [62]. Various bacterial species differentially affect MMP secretion and activation. Clinically, infections with P. aeruginosa, S. aureus, and Stenotrophomonas maltophilia are associated with the most severe form of HAP [63]. In HAP patients, high-risk pathogens appear to induce the release of strong neutrophil MMPs. In addition, Schaaf et al. observed higher MMP-8 and MMP-9 levels in the lungs, and an increased MMP-9/TIMP-1 molar ratio and MMP-9-activity compared with HAP patients with low-risk bacteria and control patients [44]. HAP patients exhibited a close correlation between pulmonary MMP levels and the laboratory parameters of systemic inflammation, such as high-serum C-reactive protein, high white blood cell counts, and high body temperature [44]. Hartog et al. observed increased levels and activity of MMP-8 and MMP-9 in plasma and in the minibronchoalveolar lavage fluid (mini-BALF) of patients with HAP, which correlated with systemic signs of inflammation [51]. MMP activation in HAP patients might be necessary for bacterial clearance, but unresolved infections might trigger ongoing MMP activation and tissue destruction [64,65]. In intensive care units, 15% to 30% of patients who are intubated and mechanically ventilated develop VAP as a complication [66]. VAP patients are known to possess dysfunctional neutrophils, which are less capable of phagocytosis and cytotoxicity, and once recruited, they can easily damage pulmonary epithelial membranes [67]. Wilkinson et al. suggested that excessive dysfunctional neutrophils are recruited to the lungs of VAP patients and active proteolytic enzymes are secreted into the alveolar space [68]. Data have indicated that expression of MMP-8 and MMP-9 significantly increased in BALF in VAP patients [61,68]. Furthermore, the imbalance between MMP-9 and TIMP-1 might indicate severe alveolar capillary damage and poor outcomes [61]. Several recent studies evaluating the MMP plasma levels in CAP patients have been performed. Our laboratory first reported that in CAP patients, the activity and level of MMP-9 in serum were significantly
275
higher compared with healthy controls. We suggested that MMP-9 may play an essential role in the pathogenesis of CAP [69,70]. In addition, MMP-9 expression may be inhibited by TIMP-1 [71]. The plasma TIMP-1 concentration was positively correlated with CAP severity, and the MMP-9/TIMP-1 molar ratio was significantly increased in patients with CAP; thus, we suggested that incorporating plasma MMP-9 levels and the MMP-9/TIMP-1 molar ratio into a clinical evaluation will aid in CAP diagnosis [72]. Lipocalin 2 (LCN2), also known as neutrophil gelatinase-associated lipocalin [73], forms a complex with MMP-9, thereby preventing the autodegradation of MMP-9 and increasing its activity [74]. We determined that the plasma level of LCN2 was correlated with the severity of CAP and significantly correlated with LCN2/ MMP-9 levels. We suggested that serum LCN2 and the LCN2/MMP-9 complex can act as adjuvant diagnostic biomarkers for CAP [75]. M. pneumoniae is a prominent etiology of CAP cases that are sufficiently severe to require hospitalization [76]. Puljiz et al. discovered that in M. pneumonia-infected CAP patients, MMP-2 plasma levels decreased in the acute phase but increased in the convalescent phase; in contrast, the MMP-9 mRNA expression in peripheral blood mononuclear cells (PBMCs) increased in the acute phase of the illness and then decreased in the convalescent phase, and the same results were observed in the MMP-9 plasma levels. They speculated that MMP-2 in the acute phase of the disease was attracted to the pulmonary compartment containing other inflammatory mediators and that PBMCs are vital sources of MMP-9 during CAP caused by M. pneumoniae [77]. MMP concentration and activation are markers for the severity of inflammation [44] and are reported to be positively correlated with pneumonia. Thus, incorporating MMPs into clinical information is beneficial to assist with the diagnosis and prognosis of CAP. Elevated levels of MMP activity and quantity were detected among three types of pneumonia subjects: MMP-2, 8, 9 in HAP; MMP-8, 9 in VAP; and MMP-2, 9 in CAP. However, the precise mechanism and prognosis to which they contribute to pneumonia requires further studies. Previous studies have shown that MMPs are essential for pulmonary epithelial immune responses (MMP-7, 10, 28); maintaining immunity by activating specific proteins (MMP-2, 3, 7, 9, 12, 28); various leukocyte migration (MMP-2, 8, 9); and killing and phagocytosis of bacteria (MMP-9), although many roles MMPs in pneumonia pathology remain unclear. In the pathology of pneumonia, MMPs are necessary in the defense against a pathogen, but it is also responsible for lung tissue damage. This might be one reason why there is no directly significant correlated result between the severity of pneumonia and MMP levels. Thus, additional studies for the development of MMPs into biomarkers for the diagnosis or prognosis of pneumonia are required. However, it is possible to determine the potential range of MMP levels, which are adequate for the immune system to work but are not excessive enough to result in severe complications. The long-term goal is to use MMP levels to evaluate the severity of pneumonia. Moreover, we may be able to suppress specific MMP expression or use inhibitors of MMPs to prevent complications in pneumonia patients who overexpress in MMPs. References [1] WHO. The top 10 causes of death; 2013. [2] Metlay JP, Fine MJ. Testing strategies in the initial management of patients with community-acquired pneumonia. Ann Intern Med 2003;138:109–18. [3] Baron EJ, Miller JM, Weinstein MP, Richter SS, Gilligan PH, Thomson Jr RB, et al. A guide to utilization of the microbiology laboratory for diagnosis of infectious diseases: 2013 recommendations by the Infectious Diseases Society of America (IDSA) and the American Society for Microbiology (ASM)(a). Clin Infect Dis 2013;57:e22-121. [4] Cheng CW, Chien MH, Su SC, Yang SF. New markers in pneumonia. Clin Chim Acta 2013;419:19–25. [5] Longo ASF, Dan L, Kasper Dennis L, Hauser Stephen L, Jameson J Larry, Loscalzo Joseph, editors. Harrison's™ Principles of internal medicine eighteenth edition; 2011. [6] Anand N, Kollef MH. The alphabet soup of pneumonia: CAP, HAP, HCAP, NHAP, and VAP. Semin Respir Crit Care Med 2009;30:3–9.
276
T.-Y. Chiang et al. / Clinica Chimica Acta 433 (2014) 272–277
[7] America. ATSIDSo. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005;171:388–416. [8] WHO. Pneumonia; 2013. [9] Jereb M, Kotar T. Usefulness of procalcitonin to differentiate typical from atypical community-acquired pneumonia. Wien Klin Wochenschr 2006;118:170–4. [10] Parks WC, Wilson CL, Lopez-Boado YS. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol 2004;4:617–29. [11] Nagase H, Woessner Jr JF. Matrix metalloproteinases. J Biol Chem 1999;274:21491–4. [12] Pardo A, Selman M. Matrix metalloproteases in aberrant fibrotic tissue remodeling. Proc Am Thorac Soc 2006;3:383–8. [13] Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 2001;17:463–516. [14] Van Wart HE, Birkedal-Hansen H. The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. Proc Natl Acad Sci U S A 1990;87:5578–82. [15] Bode W, Gomis-Ruth FX, Stockler W. Astacins, serralysins, snake venom and matrix metalloproteinases exhibit identical zinc-binding environments (HEXXHXXGXXH and Met-turn) and topologies and should be grouped into a common family, the ‘metzincins’. FEBS Lett 1993;331:134–40. [16] Khokha R, Murthy A, Weiss A. Metalloproteinases and their natural inhibitors in inflammation and immunity. Nat Rev Immunol 2013;13:649–65. [17] Bode W. A helping hand for collagenases: the haemopexin-like domain. Structure 1995;3:527–30. [18] Allan JA, Docherty AJ, Barker PJ, Huskisson NS, Reynolds JJ, Murphy G. Binding of gelatinases A and B to type-I collagen and other matrix components. Biochem J 1995;309(Pt 1):299–306. [19] Gururajan R, Grenet J, Lahti JM, Kidd VJ. Isolation and characterization of two novel metalloproteinase genes linked to the Cdc2L locus on human chromosome 1p36.3. Genomics 1998;52:101–6. [20] Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 2003;92:827–39. [21] Kheradmand F, Werner E, Tremble P, Symons M, Werb Z. Role of Rac1 and oxygen radicals in collagenase-1 expression induced by cell shape change. Science 1998;280:898–902. [22] Brenneisen P, Wenk J, Klotz LO, Wlaschek M, Briviba K, Krieg T, et al. Central role of ferrous/ferric iron in the ultraviolet B irradiation-mediated signaling pathway leading to increased interstitial collagenase (matrix-degrading metalloprotease (MMP)-1) and stromelysin-1 (MMP-3) mRNA levels in cultured human dermal fibroblasts. J Biol Chem 1998;273:5279–87. [23] Reunanen N, Foschi M, Han J, Kahari VM. Activation of extracellular signal-regulated kinase 1/2 inhibits type I collagen expression by human skin fibroblasts. J Biol Chem 2000;275:34634–9. [24] Nagase H. Activation mechanisms of matrix metalloproteinases. Biol Chem 1997;378:151–60. [25] Gill S, Wight TN, Frevert CW. Proteoglycans: key regulators of pulmonary inflammation and the innate immune response to lung infection. Anat Rec (Hoboken) 2010;293:968–81. [26] Bals R, Hiemstra PS. Innate immunity in the lung: how epithelial cells fight against respiratory pathogens. Eur Respir J 2004;23:327–33. [27] Boucher RC. New concepts of the pathogenesis of cystic fibrosis lung disease. Eur Respir J 2004;23:146–58. [28] Kassim SY, Gharib SA, Mecham BH, Birkland TP, Parks WC, McGuire JK. Individual matrix metalloproteinases control distinct transcriptional responses in airway epithelial cells infected with Pseudomonas aeruginosa. Infect Immun 2007; 75:5640–50. [29] Lopez-Boado YS, Wilson CL, Parks WC. Regulation of matrilysin expression in airway epithelial cells by Pseudomonas aeruginosa flagellin. J Biol Chem 2001;276:41417–23. [30] Manicone AM, Birkland TP, Lin M, Betsuyaku T, van Rooijen N, Lohi J, et al. Epilysin (MMP-28) restrains early macrophage recruitment in Pseudomonas aeruginosa pneumonia. J Immunol 2009;182:3866–76. [31] Li Q, Park PW, Wilson CL, Parks WC. Matrilysin shedding of syndecan-1 regulates chemokine mobilization and transepithelial efflux of neutrophils in acute lung injury. Cell 2002;111:635–46. [32] Lopez-Boado YS, Wilson CL, Hooper LV, Gordon JI, Hultgren SJ, Parks WC. Bacterial exposure induces and activates matrilysin in mucosal epithelial cells. J Cell Biol 2000;148:1305–15. [33] McGuire JK, Li Q, Parks WC. Matrilysin (matrix metalloproteinase-7) mediates E-cadherin ectodomain shedding in injured lung epithelium. Am J Pathol 2003;162:1831–43. [34] Dunsmore SE, Saarialho-Kere UK, Roby JD, Wilson CL, Matrisian LM, Welgus HG, et al. Matrilysin expression and function in airway epithelium. J Clin Invest 1998;102:1321–31. [35] Wilson CL, Ouellette AJ, Satchell DP, Ayabe T, Lopez-Boado YS, Stratman JL, et al. Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense. Science 1999;286:113–7. [36] Grassme H, Kirschnek S, Riethmueller J, Riehle A, von Kurthy G, Lang F, et al. CD95/ CD95 ligand interactions on epithelial cells in host defense to Pseudomonas aeruginosa. Science 2000;290:527–30. [37] Powell WC, Fingleton B, Wilson CL, Boothby M, Matrisian LM. The metalloproteinase matrilysin proteolytically generates active soluble Fas ligand and potentiates epithelial cell apoptosis. Curr Biol 1999;9:1441–7. [38] Nakamura M, Miyamoto S, Maeda H, Ishii G, Hasebe T, Chiba T, et al. Matrix metalloproteinase-7 degrades all insulin-like growth factor binding proteins and facilitates insulin-like growth factor bioavailability. Biochem Biophys Res Commun 2005;333:1011–6.
[39] Selman M, Pardo A. Idiopathic pulmonary fibrosis: an epithelial/fibroblastic cross-talk disorder. Respir Res 2002;3:3. [40] Wilson CL, Heppner KJ, Labosky PA, Hogan BL, Matrisian LM. Intestinal tumorigenesis is suppressed in mice lacking the metalloproteinase matrilysin. Proc Natl Acad Sci U S A 1997;94:1402–7. [41] Zuo F, Kaminski N, Eugui E, Allard J, Yakhini Z, Ben-Dor A, et al. Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans. Proc Natl Acad Sci U S A 2002;99:6292–7. [42] Yuan R, El-Asady R, Liu K, Wang D, Drachenberg CB, Hadley GA. Critical role for CD103+CD8+ effectors in promoting tubular injury following allogeneic renal transplantation. J Immunol 2005;175:2868–79. [43] Kilshaw PJ, Murant SJ. Expression and regulation of beta 7(beta p) integrins on mouse lymphocytes: relevance to the mucosal immune system. Eur J Immunol 1991;21:2591–7. [44] Schaaf B, Liebau C, Kurowski V, Droemann D, Dalhoff K. Hospital acquired pneumonia with high-risk bacteria is associated with increased pulmonary matrix metalloproteinase activity. BMC Pulm Med 2008;8:12. [45] Brown GM, Brown DM, Donaldson K, Drost E, MacNee W. Neutrophil sequestration in rat lungs. Thorax 1995;50:661–7. [46] Delclaux C, Delacourt C, D'Ortho MP, Boyer V, Lafuma C, Harf A. Role of gelatinase B and elastase in human polymorphonuclear neutrophil migration across basement membrane. Am J Respir Cell Mol Biol 1996;14:288–95. [47] Borregaard N, Cowland JB. Granules of the human neutrophilic polymorphonuclear leukocyte. Blood 1997;89:3503–21. [48] Rosendahl A, Bergmann S, Hammerschmidt S, Goldmann O, Medina E. Lung dendritic cells facilitate extrapulmonary bacterial dissemination during pneumococcal pneumonia. Front Cell Infect Microbiol 2013;3:21. [49] Opdenakker G, Van den Steen PE, Dubois B, Nelissen I, Van Coillie E, Masure S, et al. Gelatinase B functions as regulator and effector in leukocyte biology. J Leukoc Biol 2001;69:851–9. [50] Price B, Dennison C, Tschesche H, Elliott E. Neutrophil tissue inhibitor of matrix metalloproteinases-1 occurs in novel vesicles that do not fuse with the phagosome. J Biol Chem 2000;275:28308–15. [51] Hartog CM, Wermelt JA, Sommerfeld CO, Eichler W, Dalhoff K, Braun J. Pulmonary matrix metalloproteinase excess in hospital-acquired pneumonia. Am J Respir Crit Care Med 2003;167:593–8. [52] Oggioni MR, Memmi G, Maggi T, Chiavolini D, Iannelli F, Pozzi G. Pneumococcal zinc metalloproteinase ZmpC cleaves human matrix metalloproteinase 9 and is a virulence factor in experimental pneumonia. Mol Microbiol 2003;49:795–805. [53] Yamashiro S, Kamohara H, Wang JM, Yang D, Gong WH, Yoshimura T. Phenotypic and functional change of cytokine-activated neutrophils: inflammatory neutrophils are heterogeneous and enhance adaptive immune responses. J Leukoc Biol 2001; 69:698–704. [54] Taggart CC, Greene CM, Carroll TP, O'Neill SJ, McElvaney NG. Elastolytic proteases: inflammation resolution and dysregulation in chronic infective lung disease. Am J Respir Crit Care Med 2005;171:1070–6. [55] Chang SH, Dong C. IL-17F: regulation, signaling and function in inflammation. Cytokine 2009;46:7–11. [56] Kumagai K, Ohno I, Okada S, Ohkawara Y, Suzuki K, Shinya T, et al. Inhibition of matrix metalloproteinases prevents allergen-induced airway inflammation in a murine model of asthma. J Immunol 1999;162:4212–9. [57] Hong JS, Greenlee KJ, Pitchumani R, Lee SH, Song LZ, Shan M, et al. Dual protective mechanisms of matrix metalloproteinases 2 and 9 in immune defense against Streptococcus pneumoniae. J Immunol 2011;186:6427–36. [58] Shapiro SD. Elastolytic metalloproteinases produced by human mononuclear phagocytes. Potential roles in destructive lung disease. Am J Respir Crit Care Med 1994; 150:S160–4. [59] Torii K, Iida K, Miyazaki Y, Saga S, Kondoh Y, Taniguchi H, et al. Higher concentrations of matrix metalloproteinases in bronchoalveolar lavage fluid of patients with adult respiratory distress syndrome. Am J Respir Crit Care Med 1997; 155:43–6. [60] Lindberg RL, Sorsa T, Tervahartiala T, Hoffmann F, Mellanen L, Kappos L, et al. Gelatinase B [matrix metalloproteinase (MMP)-9] and collagenases (MMP-8/-13) are upregulated in cerebrospinal fluid during aseptic and bacterial meningitis in children. Neuropathol Appl Neurobiol 2006;32:304–17. [61] El-Solh AA, Amsterdam D, Alhajhusain A, Akinnusi ME, Saliba RG, Lynch SV, et al. Matrix metalloproteases in bronchoalveolar lavage fluid of patients with type III Pseudomonas aeruginosa pneumonia. J Infect 2009;59:49–55. [62] Guideline for prevention of nosocomial pneumonia. Centers for disease control and prevention. Respir Care 1994;39:1191–236. [63] Lynch III JP. Hospital-acquired pneumonia: risk factors, microbiology, and treatment. Chest 2001;119:373S–84S. [64] Zheng L, Lam WK, Tipoe GL, Shum IH, Yan C, Leung R, et al. Overexpression of matrix metalloproteinase-8 and -9 in bronchiectatic airways in vivo. Eur Respir J 2002; 20:170–6. [65] Sagel SD, Kapsner RK, Osberg I. Induced sputum matrix metalloproteinase-9 correlates with lung function and airway inflammation in children with cystic fibrosis. Pediatr Pulmonol 2005;39:224–32. [66] Chastre J, Fagon JY. Ventilator-associated pneumonia. Am J Respir Crit Care Med 2002;165:867–903. [67] Conway Morris A, Kefala K, Wilkinson TS, Dhaliwal K, Farrell L, Walsh T, et al. C5a mediates peripheral blood neutrophil dysfunction in critically ill patients. Am J Respir Crit Care Med 2009;180:19–28. [68] Wilkinson TS, Morris AC, Kefala K, O'Kane CM, Moore NR, Booth NA, et al. Ventilatorassociated pneumonia is characterized by excessive release of neutrophil proteases in the lung. Chest 2012;142:1425–32.
T.-Y. Chiang et al. / Clinica Chimica Acta 433 (2014) 272–277 [69] Yang SF, Chu SC, Chiang IC, Kuo WF, Chiou HL, Chou FP, et al. Excessive matrix metalloproteinase-9 in the plasma of community-acquired pneumonia. Clin Chim Acta 2005;352:209–15. [70] Chiang TY, Shyu LY, Tsao TC, Chien MH, Tsao SM, Lee YT, et al. Elevated plasma matrix metalloproteinase-9 protein and its gene polymorphism in patients with community-acquired pneumonia. Clin Chem Lab Med 2012;50:449–54. [71] Baker AH, Edwards DR, Murphy G. Metalloproteinase inhibitors: biological actions and therapeutic opportunities. J Cell Sci 2002;115:3719–27. [72] Chiang TY, Yu YL, Lin CW, Tsao SM, Yang SF, Yeh CB. The circulating level of MMP-9 and its ratio to TIMP-1 as a predictor of severity in patients with communityacquired pneumonia. Clin Chim Acta 2013;424:261–6. [73] Cowland JB, Borregaard N. Molecular characterization and pattern of tissue expression of the gene for neutrophil gelatinase-associated lipocalin from humans. Genomics 1997;45:17–23.
277
[74] Yan L, Borregaard N, Kjeldsen L, Moses MA. The high molecular weight urinary matrix metalloproteinase (MMP) activity is a complex of gelatinase B/MMP-9 and neutrophil gelatinase-associated lipocalin (NGAL). Modulation of MMP-9 activity by NGAL. J Biol Chem 2001;276:37258–65. [75] Yeh YH, Chang JL, Hsiao PC, Tsao SM, Lin CH, Kao SJ, et al. Circulating level of lipocalin 2 as a predictor of severity in patients with community-acquired pneumonia. J Clin Lab Anal 2013;27:253–60. [76] Waites KB, Talkington DF. Mycoplasma pneumoniae and its role as a human pathogen. Clin Microbiol Rev 2004;17:697–728. [77] Puljiz I, Markotic A, Cvetko Krajinovic L, Guzvinec M, Polasek O, Kuzman I. Mycoplasma pneumoniae in adult community-acquired pneumonia increases matrix metalloproteinase-9 serum level and induces its gene expression in peripheral blood mononuclear cells. Med Sci Monit 2012;18:CR500–5.
Contents lists available at ScienceDirect
Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Invited critical review
Matrix metalloproteinases in pneumonia☆ Ting-Yen Chiang a, Shih-Ming Tsao a,b, Chao-Bin Yeh a,c, Shun-Fa Yang d,e,⁎ a
School of Medicine, Chung Shan Medical University, Taichung, Taiwan Division of Infectious Diseases, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan c Department of Emergency Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan d Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan e Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan b
a r t i c l e
i n f o
Article history: Received 19 January 2014 Received in revised form 25 March 2014 Accepted 26 March 2014 Available online 8 April 2014 Keywords: Pneumonia Matrix metalloproteinase
a b s t r a c t Pneumonia is a worldwide infectious disease that is associated with significant morbidity and mortality and is the most common fatal infection acquired in hospitals. Despite advances in preventive strategies, such as antibiotic therapies and intensive care, the mortality rate still requires substantial improvement. Matrix metalloproteinases (MMPs) are a large family of zinc-dependent endopeptidases, which are known as the major enzymes responsible for the proteolytic degradation of proteinaceous components of the extracellular matrix (ECM). Although the main function of MMPs is the removal of the ECM during tissue resorption and progression of various diseases, MMPs also interact with multiple cytokines, participating in the pathology of infection and inflammation. This review presents a schematic overview of the different MMPs expressed in pneumonia. MMPs are key factors in the pathogenesis of various types of pneumonia, such as community-acquired pneumonia, hospital-acquired pneumonia, and ventilator-associated pneumonia. Here, we review the pathological roles of various MMPs in pneumonia. © 2014 Elsevier B.V. All rights reserved.
Contents 1. 2. 3.
Introduction to pneumonia . . . . . . . . . . . . . Three types of pneumonia . . . . . . . . . . . . . . Matrix metalloproteinases participating in the pathology of inflammation . . . . . . . . . . . . . . . . . . 4. Role of matrix metalloproteinases in pneumonia . . . . References . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
272 272
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
273 274 275
1. Introduction to pneumonia Pneumonia is associated with significant morbidity and mortality, causing the deaths of 3.2 million people in 2011 and ranking third among the 10 most common causes of death worldwide [1]. The primary method for diagnosing pneumonia is the identification of a microbiological pathogen isolated directly from lung tissue; however, this invasive procedure is not routinely performed. Performing clinical evaluations followed by chest radiography can help physicians to preliminarily ☆ The authors have declared no conflicts of interest. ⁎ Corresponding author at: Institute of Medicine, Chung Shan Medical University, 110, Section 1, Chien-Kuo N. Road, Taichung, Taiwan. Tel.: +886 4 24739595x34253; fax: +886 4 24723229. E-mail address: [email protected] (S.-F. Yang).
http://dx.doi.org/10.1016/j.cca.2014.03.031 0009-8981/© 2014 Elsevier B.V. All rights reserved.
determine pneumonia impressions [2], and laboratory techniques, such as Gram's stain, sputum cultures, blood cultures, antigen tests, polymerase chain reaction, and serology, can be used to determine the potential etiology [3]. Biological markers are occasionally used to evaluate pneumonia [4]. Thus, developing a biomarker for performing rapid and reliable diagnoses would be beneficial.
2. Three types of pneumonia Pneumonia is defined as an infection of the pulmonary parenchyma that develops from the proliferation of microbial pathogens at the alveolar level of the respiratory track and the response of the host itself [5]. Because the epidemiology, pathogenesis, and risk factors for infection of pneumonia patients are different, the American Thoracic Society
T.-Y. Chiang et al. / Clinica Chimica Acta 433 (2014) 272–277
and Infectious Diseases Society of America have developed guidelines for distinguishing among three types of pneumonia. Communityacquired pneumonia (CAP) is defined as pneumonia acquired from the community. Hospital-acquired (or nosocomial) pneumonia (HAP) is defined as pneumonia that occurs 48 h or more after hospital admission and does not appear to be incubating at the time of admission. Among HAP patients, those who develop pneumonia after more than 48 to 72 h of endotracheal intubation are classified as having ventilatorassociated pneumonia (VAP) [6,7]. The etiology of pneumonia includes bacteria, viruses, fungi, and protozoa [8]. Generally, two groups of pathogens that potentially cause pneumonia exist: “typical” bacteria, including Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and gram-negative bacilli, such as Klebsiella pneumoniae and Pseudomonas aeruginosa; and “atypical” organisms, including Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella species, and respiratory viruses, such as influenza viruses, adenoviruses, and respiratory syncytial viruses. Determining whether a case is typical or atypical pneumonia is imperative because this diagnosis provides considerable implications for therapy. However, 11–20% of pneumonia cases are polymicrobial, and the etiology often includes a combination of typical and atypical pathogens [9]. 3. Matrix metalloproteinases participating in the pathology of inflammation Matrix metalloproteinases (MMPs), which are also called matrixins, are a large family of zinc-dependent endopeptidases that are known Table 1 Classification of MMPs.
273
as the major enzymes responsible for the proteolytic degradation of proteinaceous components of the extracellular matrix (ECM) [10], which are essential for embryonic development, morphogenesis, reproduction, tissue homeostasis, tumorigenesis, and organ fibrogenesis [11, 12]. Excreted MMPs contain 23 proteases in humans and are categorized into four classes based on their substrate specificity (Table 1): collagenases (MMP-1, -8, and -13); gelatinases (MMP-2 and -9); stromelysins (MMP-3, -10, and -11); and a heterogeneous group that includes matrilysin (MMP-7), metalloelastase (MMP-12), enamelysin (MMP-20), endometase (MMP-26), and epilysin (MMP-28). The membrane MMPs (MMP-14, -15, -16, -17, -24, and -25) are anchored to the cell surface. An alternate classification system that categorizes the MMPs based on domain structure is also used [13]. MMPs typically consist of four domains: the propeptide domain, which contains a cysteine-switch motif for ligating catalytic zinc to maintain the latency of the inactive form of MMPs [14]; the catalytic domain, which contains two zinc ions that coordinate with the zincbinding motif HEXXHXXGXXH and a conserved methionine, which forms a unique Met-turn structure for stabilization [15]; and the cysteine residue in the propeptide domain interacts with the catalytic zinc ion, which prevents its association with water molecules until the propeptide domain is removed [16]. Except for MMP-7, MMP-23, and MMP-26, MMPs have C-terminal hemopexin-like domains that are recognized by substrates. The hemopexin domain consists of a four-bladed propeller structure and confers substrate specificity to the MMPs; thus, degradation of the triple-helical collagens is absolutely necessary [17].
274
T.-Y. Chiang et al. / Clinica Chimica Acta 433 (2014) 272–277
Each type of MMP contains a linker region that varies in length, and several MMPs possess slight structural differences. The gelatinases (MMP-2 and -9) contain three repeats of a fibronectin type II inserted into the catalytic domain for binding to gelatin and collagen [18]. MMP-23 contains a cysteine-rich region and an immunoglobulin domain instead of the hemopexin domain [19]. Finally, membrane-type MMPs contain a transmembrane domain or a glycosylphosphatidylinositol anchor [16, 20]. MMP function is regulated at several levels. The first level of control of MMP production is transcriptional regulation. The induction of gene expression is controlled by effectors, including growth factors, cytokines, chemical agents, physiological stress, and oncogenic cellular transformation. In addition, enhanced MMP gene expression may be downregulated by suppressive factors, such as transforming growth factor b, retinoic acids, or glucocorticoids. Moreover, specific signaling pathways result in the expression of particular MMP genes [11]. For example, activation of the Rho family guanosine triphosphatase (GTPase) pathway increased the expression of MMP-1 [21]; ultraviolet B (UVB) irradiation mediated signaling pathway up-regulates MMP-1 and MMP-3 expression [22]. Moreover, activation of the ceramide signaling pathway inhibits MMP-1 gene expression [23]. Most MMPs are translated into an inactive zymogen form. Secreted zymogens are activated either intracellularly by zymogen convertases, such as furin, in the normal secretory pathway, at the cell surface, or extracellularly by other proteases [16]. In all cases, activation requires the disruption of the Cys–Zn2+ (cysteine switch) interaction [24]. For example, in neutrophils, specific MMPs (MMP-8 or MMP-9) can be stored as proenzymes in intracellular granules, and their exocytosis is stimulated by external signals (including cytokine signaling or CD40 signaling) [16]. Finally, active MMP proteins are naturally inhibited by tissue inhibitors of metalloproteinases (TIMPs) in extracellular environments [16]. Although the main function of MMPs is the removal of the ECM during tissue resorption and the progression of various diseases, MMPs also interact with numerous cytokines, participating in the pathology of infection and inflammation [11,25]. In the pathology of pneumonia, an infectious disease, MMPs are understandable and have been shown to play a role.
4. Role of matrix metalloproteinases in pneumonia The first line of defense against invasive respiratory pathogens is the airway epithelium, and the mechanisms include the prevention of bacterial colonization and infection in the airways. Epithelial cells maintain a barrier to the environment, and provide enzymes (such as lysozyme, β-defensins, cathelicidin, and other enzymes [26]) and an airway mucus layer for physical protection [27]. In addition, they regulate inflammation as a secondary line of defense in response to infection by secreting factors that recruit inflammatory cells to attack invasive pathogens; MMPs are components of these factors [28], and several reports have described the presence of an increased epithelial MMP
expression in response to bacterial infection, such as those of MMP-7 [29], MMP-10 [28], and MMP-28 [30] (Table 2). MMP-7 and MMP-28 are constitutively expressed in low concentrations by bronchial epithelial cells and are induced by bacterial infections [30–32]. Previous studies have reported that MMP-7 has several functions involved in immune responses, which include re-epithelializing airways by cleaving E-cadherin [33,34], processing antibacterial peptides [35], regulating acute alveolar neutrophil transepithelial migration by shedding syndecan-1/KC complexes [31], clearing pathogens [36] by promoting apoptosis through the generation of soluble Fas (CD95) ligands [36,37], and regulating growth factor signaling through epidermal growth factors and insulin-like growth factors [38]. MMP-28 has been shown to control neutrophil recruitment into the lung in a P. aeruginosa pneumonia model [30]. Most MMPs play roles in maintaining immunity by cleaving specific proteins, which increases the activity of the target substrates [39]. For example, MMP-2, MMP-3, and MMP-9 can activate IL-1β [40], and MMP-7 and MMP-12 can activate latent TNFα [41–43]. In addition, MMP-28 restrains macrophage recruitment by retarding the chemotaxis of these cells [30]. Moreover, Kassim et al. demonstrated that MMP-10 restrains the inflammatory response and controls apoptosis [28]. In the lung, neutrophils are located in the vascular bed. Neutrophils are recruited to pulmonary capillaries by inflammatory cytokines, such as interleukin-8 (IL-8) and leukrotrien B4 in patients with pneumonia [44]. Subsequently, the activated MMPs contribute to neutrophil migration into the alveolar compartment [45]. The release of MMP-8 and MMP-9 [44,46] is speculated to result in a disruption of basement membrane components, which facilitates the neutrophil invasion of extravascular tissue [47]. However, Rosendahl et al. proposed that bacteria can exploit MMP-9 to open tissue barriers and cause its own dissemination from the local site of infection using an S. pneumonia-infected model [48]. In the role of degrading the tissue barriers, MMPs have two aspects in the pathology of pneumonia, it benefits the inflammatory cells to infiltrate to the infected site; simultaneously, it results in the dissemination of the pathogen. The alveolar compartment is the location where neutrophils degranulate with the exocytosis of MMPs, such as MMP-8, MMP-9 [49], as well as other types of neutrophil granules and reactive oxygen species, which can execute antimicrobial functions [50]. In pneumonia patients, compared with peripheral neutrophils, pulmonary neutrophils are highly stimulated during infections to release MMPs [51]. Released MMPs are activated by bacterial MMPs [52], plasmin [53], or other neutrophil products such as myeloperoxidase and neutrophil elastase [44,54]. Oggioni et al. discovered that a pneumococcal zinc metalloproteinase can cleave and activate MMP-9 in a murine model of pneumonia [44]. MMP-9 and MMP-2 play key roles in the migration of various leukocytes, such as T cells and neutrophils [47]. MMP-2 and, to a lesser degree, MMP-9 were observed to efficiently cleave and inactivate IL-17A, which is a pathogen-associated proinflammatory molecule that induces the recruitment of activated neutrophils to infection sites [55].
Table 2 Role of MMPs in pneumonia. MMPs
Pneumonia
MMP-2, MMP-9 MMP-2, MMP-9 MMP-7 MMP-7, MMP-10 MMP-8, MMP-9 MMP-8, MMP-9 MMP-8, MMP-9 MMP-8, MMP-9, TIMP-1 MMP-9 MMP-9, TIMP-1 MMP-9, LCN2 MMP-28
S. pneumoniae pneumonia in murine model M. pneumoniae CAP Airway epithelial cells infected with P. aeruginosa in vivo P. aeruginosa pneumonia in murine model HAP HAP with high-risk bacteria VAP P. aeruginosa VAP CAP CAP CAP P. aeruginosa pneumonia in murine model
References MMPs serves in the early host immune response MMP-9 activity elevated in M. pneumoniae CAP patients Infection induced MMP-7 expression Infection induced MMP expression MMP levels are increased in HAP patients MMP activities are elevated in HAP patients MMPs elevated in VAP patients Higher MMP-9/TIMP-1 ratio determine poor outcome MMP-9 elevated in CAP patients MMP-9/TIMP-1 ratio elevated in CAP patients LCN2/MMP-9 correlated with the CAP severity MMP-28 negative regulates macrophage recruitment
Hong et al. [57] Puljiz et al. [77] Lopez-Boado et al. [29] Kassim et al. [28] Hartog et al. [51] Schaaf et al. [44] Wilkinson et al. [68] El-Solh et al. [61] Yang et al. [69] Chiang et al. [72] Yeh et al. [75] Manicone et al. [30]
T.-Y. Chiang et al. / Clinica Chimica Acta 433 (2014) 272–277
High levels of MMP-9 in the lungs were reported to promote the infiltration of inflammatory cells [56]. Furthermore, MMP-9 is critical for effective bacterial phagocytosis and the generation of reactive oxygen species in neutrophils [57]. In addition, MMP-2 and MMP-9 have been reported to play roles in regulating adaptive immune processes by degrading ECM proteins and modifying chemokines [57]. Hong et al. elaborated that MMP-2 and MMP-9 serve as anti-inflammatory mediators by avoiding excess neutrophil recruitment to the lung, and MMP-9 is essential to neutrophil-mediated bacterial killing as well as phagocytosis. Thus, the mortality rate increased in S. pneumoniae-infected MMP-2, 9−/− mice [57]. MMPs were reported to contribute to the innate immune and adaptive immune systems. Furthermore, they were shown to be crucial factors in eliminating pathogen and protecting the host itself from its own immune system. A positive feedback loop exists between cytokines and MMPs. For example, MMP-9 cleaves IL-8 into an active form, which increases MMP-9 levels, resulting in a potent IL-8 [49]. This type of positive feedback may maintain excessive MMP activity, such as the degradation of ECM, which eventually leads to severe ECM destruction and alveolocapillary leakage accompanied by an increased risk of developing acute respiratory distress syndrome (ARDS), which is the most severe complication of pneumonia [49]. The local production of MMPs can directly alter the local tissue architecture by degrading proteins of the ECM [58]. The evidence suggests that MMPs in the lung control the pathogenesis of ARDS by disrupting structures of the basement membrane. Torii et al. reported that in ARDS patients, MMP-9 levels were correlated with 7S collagen, a marker of basement membrane disruption [59]. In such cases, inhibition of MMP activity may attenuate several crucial pathogenetic steps in the inflammatory cascade, such as preventing an acute lung injury from severe infection [60]. In the pathology of pneumonia, MMPs might have a dual effect involving the ultimate outcome, duration of exposure, site of release, and characteristics of the defending pathogen [61]. HAP is the leading cause of death among hospital-acquired infections [62]. Various bacterial species differentially affect MMP secretion and activation. Clinically, infections with P. aeruginosa, S. aureus, and Stenotrophomonas maltophilia are associated with the most severe form of HAP [63]. In HAP patients, high-risk pathogens appear to induce the release of strong neutrophil MMPs. In addition, Schaaf et al. observed higher MMP-8 and MMP-9 levels in the lungs, and an increased MMP-9/TIMP-1 molar ratio and MMP-9-activity compared with HAP patients with low-risk bacteria and control patients [44]. HAP patients exhibited a close correlation between pulmonary MMP levels and the laboratory parameters of systemic inflammation, such as high-serum C-reactive protein, high white blood cell counts, and high body temperature [44]. Hartog et al. observed increased levels and activity of MMP-8 and MMP-9 in plasma and in the minibronchoalveolar lavage fluid (mini-BALF) of patients with HAP, which correlated with systemic signs of inflammation [51]. MMP activation in HAP patients might be necessary for bacterial clearance, but unresolved infections might trigger ongoing MMP activation and tissue destruction [64,65]. In intensive care units, 15% to 30% of patients who are intubated and mechanically ventilated develop VAP as a complication [66]. VAP patients are known to possess dysfunctional neutrophils, which are less capable of phagocytosis and cytotoxicity, and once recruited, they can easily damage pulmonary epithelial membranes [67]. Wilkinson et al. suggested that excessive dysfunctional neutrophils are recruited to the lungs of VAP patients and active proteolytic enzymes are secreted into the alveolar space [68]. Data have indicated that expression of MMP-8 and MMP-9 significantly increased in BALF in VAP patients [61,68]. Furthermore, the imbalance between MMP-9 and TIMP-1 might indicate severe alveolar capillary damage and poor outcomes [61]. Several recent studies evaluating the MMP plasma levels in CAP patients have been performed. Our laboratory first reported that in CAP patients, the activity and level of MMP-9 in serum were significantly
275
higher compared with healthy controls. We suggested that MMP-9 may play an essential role in the pathogenesis of CAP [69,70]. In addition, MMP-9 expression may be inhibited by TIMP-1 [71]. The plasma TIMP-1 concentration was positively correlated with CAP severity, and the MMP-9/TIMP-1 molar ratio was significantly increased in patients with CAP; thus, we suggested that incorporating plasma MMP-9 levels and the MMP-9/TIMP-1 molar ratio into a clinical evaluation will aid in CAP diagnosis [72]. Lipocalin 2 (LCN2), also known as neutrophil gelatinase-associated lipocalin [73], forms a complex with MMP-9, thereby preventing the autodegradation of MMP-9 and increasing its activity [74]. We determined that the plasma level of LCN2 was correlated with the severity of CAP and significantly correlated with LCN2/ MMP-9 levels. We suggested that serum LCN2 and the LCN2/MMP-9 complex can act as adjuvant diagnostic biomarkers for CAP [75]. M. pneumoniae is a prominent etiology of CAP cases that are sufficiently severe to require hospitalization [76]. Puljiz et al. discovered that in M. pneumonia-infected CAP patients, MMP-2 plasma levels decreased in the acute phase but increased in the convalescent phase; in contrast, the MMP-9 mRNA expression in peripheral blood mononuclear cells (PBMCs) increased in the acute phase of the illness and then decreased in the convalescent phase, and the same results were observed in the MMP-9 plasma levels. They speculated that MMP-2 in the acute phase of the disease was attracted to the pulmonary compartment containing other inflammatory mediators and that PBMCs are vital sources of MMP-9 during CAP caused by M. pneumoniae [77]. MMP concentration and activation are markers for the severity of inflammation [44] and are reported to be positively correlated with pneumonia. Thus, incorporating MMPs into clinical information is beneficial to assist with the diagnosis and prognosis of CAP. Elevated levels of MMP activity and quantity were detected among three types of pneumonia subjects: MMP-2, 8, 9 in HAP; MMP-8, 9 in VAP; and MMP-2, 9 in CAP. However, the precise mechanism and prognosis to which they contribute to pneumonia requires further studies. Previous studies have shown that MMPs are essential for pulmonary epithelial immune responses (MMP-7, 10, 28); maintaining immunity by activating specific proteins (MMP-2, 3, 7, 9, 12, 28); various leukocyte migration (MMP-2, 8, 9); and killing and phagocytosis of bacteria (MMP-9), although many roles MMPs in pneumonia pathology remain unclear. In the pathology of pneumonia, MMPs are necessary in the defense against a pathogen, but it is also responsible for lung tissue damage. This might be one reason why there is no directly significant correlated result between the severity of pneumonia and MMP levels. Thus, additional studies for the development of MMPs into biomarkers for the diagnosis or prognosis of pneumonia are required. However, it is possible to determine the potential range of MMP levels, which are adequate for the immune system to work but are not excessive enough to result in severe complications. The long-term goal is to use MMP levels to evaluate the severity of pneumonia. Moreover, we may be able to suppress specific MMP expression or use inhibitors of MMPs to prevent complications in pneumonia patients who overexpress in MMPs. References [1] WHO. The top 10 causes of death; 2013. [2] Metlay JP, Fine MJ. Testing strategies in the initial management of patients with community-acquired pneumonia. Ann Intern Med 2003;138:109–18. [3] Baron EJ, Miller JM, Weinstein MP, Richter SS, Gilligan PH, Thomson Jr RB, et al. A guide to utilization of the microbiology laboratory for diagnosis of infectious diseases: 2013 recommendations by the Infectious Diseases Society of America (IDSA) and the American Society for Microbiology (ASM)(a). Clin Infect Dis 2013;57:e22-121. [4] Cheng CW, Chien MH, Su SC, Yang SF. New markers in pneumonia. Clin Chim Acta 2013;419:19–25. [5] Longo ASF, Dan L, Kasper Dennis L, Hauser Stephen L, Jameson J Larry, Loscalzo Joseph, editors. Harrison's™ Principles of internal medicine eighteenth edition; 2011. [6] Anand N, Kollef MH. The alphabet soup of pneumonia: CAP, HAP, HCAP, NHAP, and VAP. Semin Respir Crit Care Med 2009;30:3–9.
276
T.-Y. Chiang et al. / Clinica Chimica Acta 433 (2014) 272–277
[7] America. ATSIDSo. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005;171:388–416. [8] WHO. Pneumonia; 2013. [9] Jereb M, Kotar T. Usefulness of procalcitonin to differentiate typical from atypical community-acquired pneumonia. Wien Klin Wochenschr 2006;118:170–4. [10] Parks WC, Wilson CL, Lopez-Boado YS. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol 2004;4:617–29. [11] Nagase H, Woessner Jr JF. Matrix metalloproteinases. J Biol Chem 1999;274:21491–4. [12] Pardo A, Selman M. Matrix metalloproteases in aberrant fibrotic tissue remodeling. Proc Am Thorac Soc 2006;3:383–8. [13] Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 2001;17:463–516. [14] Van Wart HE, Birkedal-Hansen H. The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. Proc Natl Acad Sci U S A 1990;87:5578–82. [15] Bode W, Gomis-Ruth FX, Stockler W. Astacins, serralysins, snake venom and matrix metalloproteinases exhibit identical zinc-binding environments (HEXXHXXGXXH and Met-turn) and topologies and should be grouped into a common family, the ‘metzincins’. FEBS Lett 1993;331:134–40. [16] Khokha R, Murthy A, Weiss A. Metalloproteinases and their natural inhibitors in inflammation and immunity. Nat Rev Immunol 2013;13:649–65. [17] Bode W. A helping hand for collagenases: the haemopexin-like domain. Structure 1995;3:527–30. [18] Allan JA, Docherty AJ, Barker PJ, Huskisson NS, Reynolds JJ, Murphy G. Binding of gelatinases A and B to type-I collagen and other matrix components. Biochem J 1995;309(Pt 1):299–306. [19] Gururajan R, Grenet J, Lahti JM, Kidd VJ. Isolation and characterization of two novel metalloproteinase genes linked to the Cdc2L locus on human chromosome 1p36.3. Genomics 1998;52:101–6. [20] Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 2003;92:827–39. [21] Kheradmand F, Werner E, Tremble P, Symons M, Werb Z. Role of Rac1 and oxygen radicals in collagenase-1 expression induced by cell shape change. Science 1998;280:898–902. [22] Brenneisen P, Wenk J, Klotz LO, Wlaschek M, Briviba K, Krieg T, et al. Central role of ferrous/ferric iron in the ultraviolet B irradiation-mediated signaling pathway leading to increased interstitial collagenase (matrix-degrading metalloprotease (MMP)-1) and stromelysin-1 (MMP-3) mRNA levels in cultured human dermal fibroblasts. J Biol Chem 1998;273:5279–87. [23] Reunanen N, Foschi M, Han J, Kahari VM. Activation of extracellular signal-regulated kinase 1/2 inhibits type I collagen expression by human skin fibroblasts. J Biol Chem 2000;275:34634–9. [24] Nagase H. Activation mechanisms of matrix metalloproteinases. Biol Chem 1997;378:151–60. [25] Gill S, Wight TN, Frevert CW. Proteoglycans: key regulators of pulmonary inflammation and the innate immune response to lung infection. Anat Rec (Hoboken) 2010;293:968–81. [26] Bals R, Hiemstra PS. Innate immunity in the lung: how epithelial cells fight against respiratory pathogens. Eur Respir J 2004;23:327–33. [27] Boucher RC. New concepts of the pathogenesis of cystic fibrosis lung disease. Eur Respir J 2004;23:146–58. [28] Kassim SY, Gharib SA, Mecham BH, Birkland TP, Parks WC, McGuire JK. Individual matrix metalloproteinases control distinct transcriptional responses in airway epithelial cells infected with Pseudomonas aeruginosa. Infect Immun 2007; 75:5640–50. [29] Lopez-Boado YS, Wilson CL, Parks WC. Regulation of matrilysin expression in airway epithelial cells by Pseudomonas aeruginosa flagellin. J Biol Chem 2001;276:41417–23. [30] Manicone AM, Birkland TP, Lin M, Betsuyaku T, van Rooijen N, Lohi J, et al. Epilysin (MMP-28) restrains early macrophage recruitment in Pseudomonas aeruginosa pneumonia. J Immunol 2009;182:3866–76. [31] Li Q, Park PW, Wilson CL, Parks WC. Matrilysin shedding of syndecan-1 regulates chemokine mobilization and transepithelial efflux of neutrophils in acute lung injury. Cell 2002;111:635–46. [32] Lopez-Boado YS, Wilson CL, Hooper LV, Gordon JI, Hultgren SJ, Parks WC. Bacterial exposure induces and activates matrilysin in mucosal epithelial cells. J Cell Biol 2000;148:1305–15. [33] McGuire JK, Li Q, Parks WC. Matrilysin (matrix metalloproteinase-7) mediates E-cadherin ectodomain shedding in injured lung epithelium. Am J Pathol 2003;162:1831–43. [34] Dunsmore SE, Saarialho-Kere UK, Roby JD, Wilson CL, Matrisian LM, Welgus HG, et al. Matrilysin expression and function in airway epithelium. J Clin Invest 1998;102:1321–31. [35] Wilson CL, Ouellette AJ, Satchell DP, Ayabe T, Lopez-Boado YS, Stratman JL, et al. Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense. Science 1999;286:113–7. [36] Grassme H, Kirschnek S, Riethmueller J, Riehle A, von Kurthy G, Lang F, et al. CD95/ CD95 ligand interactions on epithelial cells in host defense to Pseudomonas aeruginosa. Science 2000;290:527–30. [37] Powell WC, Fingleton B, Wilson CL, Boothby M, Matrisian LM. The metalloproteinase matrilysin proteolytically generates active soluble Fas ligand and potentiates epithelial cell apoptosis. Curr Biol 1999;9:1441–7. [38] Nakamura M, Miyamoto S, Maeda H, Ishii G, Hasebe T, Chiba T, et al. Matrix metalloproteinase-7 degrades all insulin-like growth factor binding proteins and facilitates insulin-like growth factor bioavailability. Biochem Biophys Res Commun 2005;333:1011–6.
[39] Selman M, Pardo A. Idiopathic pulmonary fibrosis: an epithelial/fibroblastic cross-talk disorder. Respir Res 2002;3:3. [40] Wilson CL, Heppner KJ, Labosky PA, Hogan BL, Matrisian LM. Intestinal tumorigenesis is suppressed in mice lacking the metalloproteinase matrilysin. Proc Natl Acad Sci U S A 1997;94:1402–7. [41] Zuo F, Kaminski N, Eugui E, Allard J, Yakhini Z, Ben-Dor A, et al. Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans. Proc Natl Acad Sci U S A 2002;99:6292–7. [42] Yuan R, El-Asady R, Liu K, Wang D, Drachenberg CB, Hadley GA. Critical role for CD103+CD8+ effectors in promoting tubular injury following allogeneic renal transplantation. J Immunol 2005;175:2868–79. [43] Kilshaw PJ, Murant SJ. Expression and regulation of beta 7(beta p) integrins on mouse lymphocytes: relevance to the mucosal immune system. Eur J Immunol 1991;21:2591–7. [44] Schaaf B, Liebau C, Kurowski V, Droemann D, Dalhoff K. Hospital acquired pneumonia with high-risk bacteria is associated with increased pulmonary matrix metalloproteinase activity. BMC Pulm Med 2008;8:12. [45] Brown GM, Brown DM, Donaldson K, Drost E, MacNee W. Neutrophil sequestration in rat lungs. Thorax 1995;50:661–7. [46] Delclaux C, Delacourt C, D'Ortho MP, Boyer V, Lafuma C, Harf A. Role of gelatinase B and elastase in human polymorphonuclear neutrophil migration across basement membrane. Am J Respir Cell Mol Biol 1996;14:288–95. [47] Borregaard N, Cowland JB. Granules of the human neutrophilic polymorphonuclear leukocyte. Blood 1997;89:3503–21. [48] Rosendahl A, Bergmann S, Hammerschmidt S, Goldmann O, Medina E. Lung dendritic cells facilitate extrapulmonary bacterial dissemination during pneumococcal pneumonia. Front Cell Infect Microbiol 2013;3:21. [49] Opdenakker G, Van den Steen PE, Dubois B, Nelissen I, Van Coillie E, Masure S, et al. Gelatinase B functions as regulator and effector in leukocyte biology. J Leukoc Biol 2001;69:851–9. [50] Price B, Dennison C, Tschesche H, Elliott E. Neutrophil tissue inhibitor of matrix metalloproteinases-1 occurs in novel vesicles that do not fuse with the phagosome. J Biol Chem 2000;275:28308–15. [51] Hartog CM, Wermelt JA, Sommerfeld CO, Eichler W, Dalhoff K, Braun J. Pulmonary matrix metalloproteinase excess in hospital-acquired pneumonia. Am J Respir Crit Care Med 2003;167:593–8. [52] Oggioni MR, Memmi G, Maggi T, Chiavolini D, Iannelli F, Pozzi G. Pneumococcal zinc metalloproteinase ZmpC cleaves human matrix metalloproteinase 9 and is a virulence factor in experimental pneumonia. Mol Microbiol 2003;49:795–805. [53] Yamashiro S, Kamohara H, Wang JM, Yang D, Gong WH, Yoshimura T. Phenotypic and functional change of cytokine-activated neutrophils: inflammatory neutrophils are heterogeneous and enhance adaptive immune responses. J Leukoc Biol 2001; 69:698–704. [54] Taggart CC, Greene CM, Carroll TP, O'Neill SJ, McElvaney NG. Elastolytic proteases: inflammation resolution and dysregulation in chronic infective lung disease. Am J Respir Crit Care Med 2005;171:1070–6. [55] Chang SH, Dong C. IL-17F: regulation, signaling and function in inflammation. Cytokine 2009;46:7–11. [56] Kumagai K, Ohno I, Okada S, Ohkawara Y, Suzuki K, Shinya T, et al. Inhibition of matrix metalloproteinases prevents allergen-induced airway inflammation in a murine model of asthma. J Immunol 1999;162:4212–9. [57] Hong JS, Greenlee KJ, Pitchumani R, Lee SH, Song LZ, Shan M, et al. Dual protective mechanisms of matrix metalloproteinases 2 and 9 in immune defense against Streptococcus pneumoniae. J Immunol 2011;186:6427–36. [58] Shapiro SD. Elastolytic metalloproteinases produced by human mononuclear phagocytes. Potential roles in destructive lung disease. Am J Respir Crit Care Med 1994; 150:S160–4. [59] Torii K, Iida K, Miyazaki Y, Saga S, Kondoh Y, Taniguchi H, et al. Higher concentrations of matrix metalloproteinases in bronchoalveolar lavage fluid of patients with adult respiratory distress syndrome. Am J Respir Crit Care Med 1997; 155:43–6. [60] Lindberg RL, Sorsa T, Tervahartiala T, Hoffmann F, Mellanen L, Kappos L, et al. Gelatinase B [matrix metalloproteinase (MMP)-9] and collagenases (MMP-8/-13) are upregulated in cerebrospinal fluid during aseptic and bacterial meningitis in children. Neuropathol Appl Neurobiol 2006;32:304–17. [61] El-Solh AA, Amsterdam D, Alhajhusain A, Akinnusi ME, Saliba RG, Lynch SV, et al. Matrix metalloproteases in bronchoalveolar lavage fluid of patients with type III Pseudomonas aeruginosa pneumonia. J Infect 2009;59:49–55. [62] Guideline for prevention of nosocomial pneumonia. Centers for disease control and prevention. Respir Care 1994;39:1191–236. [63] Lynch III JP. Hospital-acquired pneumonia: risk factors, microbiology, and treatment. Chest 2001;119:373S–84S. [64] Zheng L, Lam WK, Tipoe GL, Shum IH, Yan C, Leung R, et al. Overexpression of matrix metalloproteinase-8 and -9 in bronchiectatic airways in vivo. Eur Respir J 2002; 20:170–6. [65] Sagel SD, Kapsner RK, Osberg I. Induced sputum matrix metalloproteinase-9 correlates with lung function and airway inflammation in children with cystic fibrosis. Pediatr Pulmonol 2005;39:224–32. [66] Chastre J, Fagon JY. Ventilator-associated pneumonia. Am J Respir Crit Care Med 2002;165:867–903. [67] Conway Morris A, Kefala K, Wilkinson TS, Dhaliwal K, Farrell L, Walsh T, et al. C5a mediates peripheral blood neutrophil dysfunction in critically ill patients. Am J Respir Crit Care Med 2009;180:19–28. [68] Wilkinson TS, Morris AC, Kefala K, O'Kane CM, Moore NR, Booth NA, et al. Ventilatorassociated pneumonia is characterized by excessive release of neutrophil proteases in the lung. Chest 2012;142:1425–32.
T.-Y. Chiang et al. / Clinica Chimica Acta 433 (2014) 272–277 [69] Yang SF, Chu SC, Chiang IC, Kuo WF, Chiou HL, Chou FP, et al. Excessive matrix metalloproteinase-9 in the plasma of community-acquired pneumonia. Clin Chim Acta 2005;352:209–15. [70] Chiang TY, Shyu LY, Tsao TC, Chien MH, Tsao SM, Lee YT, et al. Elevated plasma matrix metalloproteinase-9 protein and its gene polymorphism in patients with community-acquired pneumonia. Clin Chem Lab Med 2012;50:449–54. [71] Baker AH, Edwards DR, Murphy G. Metalloproteinase inhibitors: biological actions and therapeutic opportunities. J Cell Sci 2002;115:3719–27. [72] Chiang TY, Yu YL, Lin CW, Tsao SM, Yang SF, Yeh CB. The circulating level of MMP-9 and its ratio to TIMP-1 as a predictor of severity in patients with communityacquired pneumonia. Clin Chim Acta 2013;424:261–6. [73] Cowland JB, Borregaard N. Molecular characterization and pattern of tissue expression of the gene for neutrophil gelatinase-associated lipocalin from humans. Genomics 1997;45:17–23.
277
[74] Yan L, Borregaard N, Kjeldsen L, Moses MA. The high molecular weight urinary matrix metalloproteinase (MMP) activity is a complex of gelatinase B/MMP-9 and neutrophil gelatinase-associated lipocalin (NGAL). Modulation of MMP-9 activity by NGAL. J Biol Chem 2001;276:37258–65. [75] Yeh YH, Chang JL, Hsiao PC, Tsao SM, Lin CH, Kao SJ, et al. Circulating level of lipocalin 2 as a predictor of severity in patients with community-acquired pneumonia. J Clin Lab Anal 2013;27:253–60. [76] Waites KB, Talkington DF. Mycoplasma pneumoniae and its role as a human pathogen. Clin Microbiol Rev 2004;17:697–728. [77] Puljiz I, Markotic A, Cvetko Krajinovic L, Guzvinec M, Polasek O, Kuzman I. Mycoplasma pneumoniae in adult community-acquired pneumonia increases matrix metalloproteinase-9 serum level and induces its gene expression in peripheral blood mononuclear cells. Med Sci Monit 2012;18:CR500–5.