Pleiotropic effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors in pulmonary diseases: A comprehensive review

Pulmonary Pharmacology & Therapeutics 30 (2015) 134e140

Contents lists available at ScienceDirect

Pulmonary Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/ypupt

Pleiotropic effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors in pulmonary diseases: A comprehensive review Rama K. Krishna a, Omar Issa b, Debjit Saha b, Francisco Yuri B. Macedo c, Barbara Correal b, Orlando Santana a, * a b c

Columbia University Division of Cardiology, Mount Sinai Medical Center, Miami Beach, FL, USA Department of Internal Medicine Mount Sinai Medical Center, Miami Beach, FL, USA Division of Cardiology Baylor College of Medicine, Houston, TX, USA

a r t i c l e i n f o

a b s t r a c t

Article history: Received 17 April 2014 Received in revised form 14 August 2014 Accepted 18 August 2014 Available online 27 August 2014

The 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) are used extensively in the treatment of hyperlipidemia. They have also demonstrated a secondary benefit in a variety of other disease processes, actions which are known as pleiotropic effects. Review of the current pulmonary literature suggests a potential advantage of statin usage in a variety of pulmonary conditions. Our paper serves as a focused discussion on the pleiotropic effects of statins in the most common pulmonary disorders. © 2014 Published by Elsevier Ltd.

Keywords: Statins Pleiotropic effects Pulmonary disease Comprehensive review

1. Introduction Statins are important drugs in the treatment of hyperlipidemia, and are currently used in primary and secondary prevention of coronary artery disease and stroke. [1,2]. In addition to the benefits of using statins for hyperlipidemia and stabilization of cholesterol plaques, they have been shown to have important pleiotropic, or secondary, effects independent of their cholesterol-lowering properties [3e5]. These pleiotropic effects are a direct result of their action as inhibitors of cholesterol and isoprenoid synthesis, compounds which are ultimately responsible for the modulation of important pathways in several diseases. The upregulation of endothelial nitric oxide synthase and decreased production of nicotinamide adenine dinucleotide phosphate-oxidase that occurs with statin use enhances vascular endothelial function, reduces the amount of reactive oxidant species, and can improve the pathophysiologic responses in certain diseases [6]. Down-regulation of pro-inflammatory cytokines, immunomodulation, plaque stabilization, normalization of sympathetic outflow, decreased activation

* Corresponding author. Echocardiography Laboratory, Columbia University Division of Cardiology, Mount Sinai Medical Center, 4300 Alton Road, Miami Beach, FL 33140, USA. Tel.: þ1 305 674 2168; fax: þ1 305 674 2368. E-mail address: [email protected] (O. Santana). http://dx.doi.org/10.1016/j.pupt.2014.08.006 1094-5539/© 2014 Published by Elsevier Ltd.

of the blood coagulation cascade, and inhibition of platelet aggregation have also been proposed as possible mechanisms for statin pleiotropy (Fig. 1) [7]. Evidence suggests that statins may play an important role in the treatment of some of the most prevalent pulmonary disorders due to their effect on structural cells and inflammation. The following is a comprehensive review of the current literature regarding the potential therapeutic benefits and pleiotropic effects of statins in pulmonary pathology. 2. Chronic obstructive pulmonary disease In patients with chronic obstructive pulmonary disease (COPD), beta-agonist inhalers and steroids provide symptomatic relief rather than working to restore the patient's normal lung function [8]. The hallmark of this disease is a progressive airflow limitation resulting from parenchymal destruction, as well as, small airway obstruction from smooth muscle hypertrophy and airway fibrosis [9]. COPD is not a disease restricted to the lungs but rather a systemic illness associated with progressive muscle wasting, decreased exercise capacity, accelerated coronary artery disease, osteoporosis, and anemia [10]. The benefits on mortality with current therapy are limited [11], possibly owing to the sparing effect on neutrophil or macrophage derived inflammation which plays an important role in COPD [12].

R.K. Krishna et al. / Pulmonary Pharmacology & Therapeutics 30 (2015) 134e140

135

Fig. 1. Cholesterol synthesis pathway: Statins inhibiting HMG-CoA reductase and decreasing the synthesis of prenlylated proteins and thereby also inhibit inflammatory and free radical biomarkers.

Studies have addressed the close inverse relationship between C-reactive protein (CRP) and lung function, as well as the direct relationship between levels of CRP and the severity of COPD [10]. In the National Health and Nutrition Examination Survey III study, those patients with severe airway obstruction were twice as likely to have an elevated CRP value. There was also an additive effect between the presence of moderate-severe COPD and elevated CRP on the risk of cardiac injury [13]. Furthermore, smoking initiates an increase in cytokine interleukin (IL)-6 and IL-8, which might underlie the systemic “spill over” and pulmonary inflammation seen in this disease state [14]. This may explain why those patients with COPD have been observed to have a greater than two-fold risk of coronary artery disease [13]. There are data that suggest that statins have immune modulatory effects that could attenuate the inflammatory effects of smoking on the lungs [15]. These effects include reducing neutrophil migration, cytokine production, adverse matrix remodeling, and small airways inflammation [16]. As neutrophil mediated inflammation plays a central role in the lung damage caused by smoking in COPD [17], the benefits of statins may be additive to that of inhaled steroids. Persistence of neutrophils in COPD due to inhibition of neutrophil apoptosis and/or phagocytic clearance, might also be relevant to attenuating inflammation [18]. There are observational studies suggesting that patients with COPD that take statins have reduced hospitalization for COPD exacerbations, a lower mortality from COPD exacerbations, and a lower cardiovascular mortality when compared with patients not taking statins [19,20]. In a non-randomized study of lung function screening in smokers and ex-smokers with mild COPD, the group on statins had a 37% reduction in COPD related hospitalization, as well as, a significantly reduced forced expiratory volume in 1 s

(FEV1) decline (þ5 ml/year) when compared with those not on a statin (86 ml/year) [21]. The observation that statins attenuate FEV1 decline and may be beneficial as first line therapy in COPD patients comes from a subpopulation analysis of the Normative Aging Study, involving 803 men and 2136 FEV1 measurements over a 10 year follow-up period [22]. Across a wide range of baseline lung function, the average yearly decline in FEV1 was 24 ml/year in those not on statins and 11 ml/year in those on statins (p < 0.05). This effect was found regardless of smoking status, suggesting a benefit for both smokers and ex-smokers. In a seven year Taiwanese cohort study, statins were associated with reduced hospitalization due to COPD in 6252 patients newly diagnosed with COPD [23]. There are also three randomized controlled trials that have demonstrated positive outcomes in COPD patients who received statin therapy, by decreasing the risk of thrombotic events, which are more prevalent in COPD patients [24], improving functional capacity [25], and decreasing inflammatory markers [26]. A randomized, placebo-controlled study by the Heart Protection Study Collaborative Group demonstrated a trend towards reduced respiratory death by 30%, and reduced rates of COPD exacerbations by 20% in those patients taking statins when compared with placebo [27]. Similarly, a more recent analysis showed that statin use is associated with a beneficial effect on all-cause mortality in COPD, depending on the baseline level of systemic inflammation [28]. The results showed that long-term statin use was associated with a 78% reduction in mortality if hsCRP level is > 3 mg/L at baseline, compared with a non-significant 21% reduction in mortality if hsCRP level is  3 mg/L. Additionally, a cohort study from New Zealand demonstrated that statin use is associated with a 30% reduction in all-cause mortality at 3e4 years after first admission

136

R.K. Krishna et al. / Pulmonary Pharmacology & Therapeutics 30 (2015) 134e140

for COPD, irrespective of a past history of cardiovascular disease and diabetes mellitus [29]. Although, the evidence suggests that statins may have a beneficial role in patients with COPD, this was refuted by the results of the trial Simvastatin in the Prevention of COPD Exacerbation (STATCOPE) [30]. This was a prospective study of 885 patients, treated from 12 to 36 months, which were randomized to simvastatin 40 mg/day vs placebo. The study demonstrated that simvastatin did not impact the rate of COPD exacerbation, time to first exacerbation, or severity of exacerbation in patients with moderate to severe COPD. At this point it is unclear if statins reduce morbidity and/or mortality in patients with COPD. 3. Asthma While there is evidence that statins may be beneficial in patients with COPD this does not appear to be the case in patients with asthma where the benefits of statin usage are controversial despite positive experimental studies. In laboratory animals, statins have shown an immune-modulatory effect on allergic lung inflammation mainly by decreasing inflammatory cytokines, stabilization of eosinophilic membranes, decreasing free radical production [31], suppression of T helper (Th)1 cell development, and promotion of Th2 polarization from CD4 cells in vitro [32]. McKay et al., showed that simvastatin improved eosinophil driven inflammation in a murine model of asthma that was mediated by suppressing T lymphocyte secretion of IL-4 and IL-5 [33]. Pravastatin has also been demonstrated to attenuate cell proliferation, IL5 production, and eosinophilic airway inflammation mediated by IL-17 [34]. Human trials evaluating statins in the therapy of asthma showed either negative, or perhaps, modest benefit. A one month, randomized, placebo controlled trial of simvastatin in 16 patients with asthma, demonstrated no improvement in asthma symptoms, pulmonary function tests, or measures of inflammatory markers [35]. These findings were similar to another randomized controlled trial of atorvastatin 40 mg/day added to inhaled corticosteroids compared with inhaled corticosteroids alone in 54 adults with allergic asthma [36]. Additionally, a study using simvastatin 40 mg at night to evaluate the fluticasone sparing effect of statin treatment showed no clinically significant steroid-sparing effect in patients with eosinophilic asthma [37]. Another randomized controlled trial evaluating the effects of atorvastatin 40 mg/day vs placebo for 4 weeks, in smokers with mild to moderate asthma, also failed to show benefits in the early morning expiratory flow volumes and in inflammatory biomarkers in induced sputum [38]. It appears that statins have little or no effect on disease modification or steroid sparing in the treatment of asthma. 4. Pulmonary sarcoidosis The data concerning the use of statins in either experimental or clinical pulmonary sarcoidosis are very limited. There is an ongoing randomized, double blind, and placebo controlled trial as a phase II study, which is estimated to stop enrolling patients in December 2015 [39]. It has been enrolling patients between the ages of 18 and 70. The primary endpoint of the study is to determine whether atorvastatin administration results in less steroid use and longer steroid-free intervals in patients with pulmonary sarcoidosis who require prednisone treatment. 5. Lung malignancy Statins are being investigated as possible therapeutic agents for lung cancer based on their activity on cancer cell lines. Park

et al., demonstrated that in non-small cell lung cancer cells with a Kras mutation, gefitinib treatment in combination with lovastatin can help overcome chemotherapy-induced resistance by down regulating the Ras protein, thus blunting tumor growth pathway activation [40]. Additionally, statins may sensitize lung cancer cells to the effects of chemotherapy and ionizing radiation by impairing various growth factors and inducing the apoptosis of cancer cells via the inhibition of the Akt pathway, which plays a major role in tumor cell proliferation, survival, and invasiveness [40]. Other studies have shown that statins modulate the activity of tumor suppressors, pro-inflammatory proteases, and cell cycle regulatory proteins inhibiting the formation of lung cancer cells [41e43]. Clinical data regarding the use of statins as anti-tumor agents in lung cancer has been limited with mixed results. In a retrospective study involving 483,733 patients enrolled in the Veterans Integrated Service Network from 1998 to 2004, it was noted that patients taking statins for more than 6 months had a 55% reduction in the development of lung cancer [44]. Similarly, Van Getsel et al., analyzed 1310 patients with COPD and found that statin users had a trend towards lower risk of lung or extra pulmonary cancer mortality compared with non-users [45]. However, a phase II trial consisting of 61 patients with untreated extensive small-cell lung cancer given 40 mg of simvastatin daily along with irinotecan and cisplatin chemotherapy failed to show any benefit in 1-year survival [46]. 6. Pulmonary arterial hypertension The key pathological mechanism involved in pulmonary arterial hypertension (PAH) is a progressive arterial vasoconstriction leading to a sustained increase in pulmonary vascular resistance and pulmonary arterial pressure with further right ventricular compromise resulting in both respiratory and heart failure [47]. This vasoconstriction is a result of an imbalanced production of arterial vasodilators, such as nitric oxide and pro-stacyclin, and vasoconstrictors such as endothelin-1 and serotonin, as well as vascular remodeling and thrombus formation due to endothelial dysfunction and platelet aggregation [48]. Several treatment strategies have been suggested such as anticoagulants, prostacyclin analogs, oxygen, diuretics, digoxin, calcium channel blockers, endothelin receptor antagonists, nitric oxide, phosphodiesterase-5 inhibitors, elastase inhibitors, gene therapy, and ultimately lung transplantation. However, despite the therapeutic options available, this condition portends a poor prognosis [49]. Statins have been studied as a potential therapy for pulmonary hypertension due to the associated improvement of endothelial function, induction of vascular cell apoptosis, as well as the decrease in oxidative stress and inflammation. Additionally, statins may provide benefit by way of their inhibition of the thrombogenic response, which may be partially due to a reduction in the synthesis of isoprenoids, which are involved in the posttranslational prenylation of several proteins (Ras, Rho, and Rac). The RhoA/Rhokinase has been implicated in PAH pathogenesis along with oxidative stress and inflammation [50]. It has been proposed that statins may also ameliorate PAH via inhibition of the described pathway, as well as anti-inflammatory, antioxidant and antithrombotic actions [51]. In experimental models, simvastatin has been demonstrated to reduce the mean pulmonary arterial, and the right ventricular systolic pressure, as well as, decrease the right ventricular, left ventricular, and interventricular septal weight. Simvastatin has also been shown to improve pulmonary vascular remodeling via reduced proliferation and increased apoptosis of smooth muscle cells and endothelial cells, as well as inhibition of adventitial

R.K. Krishna et al. / Pulmonary Pharmacology & Therapeutics 30 (2015) 134e140

fibroblast proliferation, and improvement in oxidative stress [52e57]. Similar findings have been noted in animals treated with atorvastatin [58e61]. Also, in acute pulmonary embolism induced pulmonary hypertension, pre-treatment with atorvastatin resulted in a significant increase in 24 h survival rate [61,62]. Other statins (pravastatin, fluvastatin and rosuvastatin) have also shown efficacy in reducing right ventricular hypertrophy, vascular remodeling, endothelial dysfunction, and several molecular mediators present in the pathophysiology of PAH. Four studies, one observational and three randomized controlled trials, have addressed the efficacy and safety of statins usage in PAH. In an observational study, 16 patients with either primary or secondary PAH showed improvements in the 6 min walk test, cardiac output, and echocardiographic estimates of right ventricular systolic pressure, with improvement in disease progression. In a randomized, double blind, placebo controlled trial with simvastatin 42 patients were randomized to simvastatin therapy for six months in addition to sildenafil and/or endothelin-1 antagonist treatment. At six months, right ventricular mass and brain natriuretic peptide were decreased in patients who received simvastatin when compared with placebo [63]. Rosuvastatin was evaluated in a randomized, double-blind, placebo controlled trial in COPD and PAH patients. The 53 patients that were randomly assigned to pravastatin therapy showed increases in the exercise time by 52%, significant decreases in systolic pulmonary arterial pressure, and a decrease in urinary endothelin-1 levels when compared to placebo [25]. However, a randomized controlled trial in patients with PAH failed to show a benefit with the use of simvastatin 40 mg and aspirin on the 6 min walking test and biomarkers of endothelial dysfunction [64]. Overall, statins seem to benefit patients with pulmonary arterial hypertension based on the few small randomized controlled trials. However, the data are limited and more investigation is required to assess its benefit in patients with PAH. 7. Acute lung injury/acute respiratory distress syndrome Statins have also been proposed as a treatment for acute lung injury/acute respiratory distress syndrome (ALI/ARDS) based on animal models suggesting that statins can improve organ dysfunction by reducing vascular leak and inflammation [65]. In human subjects, a prospective cohort study showed a nonsignificant trend towards lower odds of death in ARDS patients receiving a statin during their intensive care unit admission [66]. In contrast, a retrospective cohort study showed no difference in mortality or organ dysfunction in ARDS patients treated with statins [67]. The Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary (HARP) dysfunction study investigated 60 patients with ALI, demonstrated that simvastatin 80 mg was safe and showed modest improvement in pulmonary function in patients who remained ventilated at 14 days [68]. The trial demonstrated that the use of simvastatin was associated with an early reduction in pulmonary and systemic inflammation evidenced by bronchoalveolar lavage IL-6, IL-8, and plasma CRP reduction. However, a multicenter, prospective study, randomized patients to receive rosuvastatin vs placebo, in patients with sepsis associated ARDS [69]. Rosuvastatin did not improve clinical outcomes in patients with sepsis associated ARDS, and the study was stopped because of futility after 745 of an estimated 1000 patients had been enrolled. Thus far, the data are equivocal with respect to the benefit of statin use in ALI and we await the results of the HARP 2 trial, which will be a phase II, single centre, prospective, double-blind, randomized, placebo-controlled trial utilizing simvastatin.

137

8. Interstitial lung disease There are observational studies that correlate statin use with the incidence of interstitial lung disease (ILD). It is estimated that for every 10,000 reports of a statin-associated adverse event, approximately 1e40 reports were for ILD [70]. The association of statin use and ILD was first reported with the use of simvastatin, however it has subsequently been reported with the use of pravastatin, fluvastatin and atorvastatin [71e73]. In a retrospective study involving 2115 smokers, statin users had a 60% increase in their odds to have ILD, after adjustment for relevant covariates including a history of high cholesterol or coronary artery disease [74]. However, the authors of the study concluded that “while our study raises concerns about the potential role for statins in the development and/or progression of ILD, these risks likely do not outweigh the substantial benefits of statin therapy in patients with cardiovascular disease”. Therefore, the use of statins in patients with ILD needs to be individualized. 9. Pneumonia The inpatient mortality for community acquired pneumonia is approximately 10% [75]. The mortality in these patients appears to be linked to an increase in systemic and pulmonary inflammation, acute lung injury, vascular dysfunction, and coagulopathy [75,76]. Although, the mechanism is not entirely clear, prior statin use may be associated with a reduced risk of developing pneumonia. A case controlled study with more than 20,000 diabetic patients, compared 4719 patients with pneumonia and 15,322 patients without pneumonia, and found an odds ratio of 0.49 (0.35e0.69) suggesting a protective effect of statins after adjusting for confounders [77]. A similarly designed study matched 1253 patients with pneumonia to 4838 control subjects, and found that current statin users had a significantly reduced risk of fatal pneumonia (adjusted odds ratio 0.47, 95% confidence interval 0.25e0.88) [78]. Another study, which was a population-based caseecontrol trial, demonstrated similar results, with an odds ratio of 0.78 (0.65e0.94) in the reduction of the development of community acquired pneumonia, and a reduced risk of short and long term mortality in patients treated with statins [79]. Not only has there been a reduction in mortality reported with the use of statins in patients with community acquired pneumonia [80e82], but also reductions in the development of complicated para-pneumonic effusions and empyema [83]. Subsequent data, however, have disputed the above findings. A systematic review and meta-analysis of observational studies, demonstrated that the benefits of statins in preventing pneumonia are inconsistent, and of low magnitude [84]. Also, a randomized, placebo-controlled, double-blinded, multicenter trial on ventilator associated pneumonia failed to show a mortality benefit with the use of simvastatin at 28 days follow up [85]. Presently, the data are too inconsistent to make any firm conclusions concerning the use of statins in patients with pneumonia. 10. Lung transplantation Data evaluating statins in patients undergoing lung transplantation are limited. A prospective study of 200 patients, who survived more than 30 days after lung transplantation, compared 39 patients on statins with 161 not on statins [86]. The study noted that acute rejection was less frequent in the statin group (15.1% vs 25.6% of biopsies, p < 0.01) and none of the 15 subjects started on statins during post-operative year one developed obliterative bronchiolitis, whereas this complication occurred in 37% of the control subjects (p < 0.01). Amongst double lung recipients, those

138

R.K. Krishna et al. / Pulmonary Pharmacology & Therapeutics 30 (2015) 134e140

taking statins had significantly better spirometry results which included: forced vital capacity (FVC) (80 ± 2% vs 70 ± 1%) and FEV1 (87 ± 2 vs 70 ± 1%), as percentages of predicted values, and absolute FEV1/FVC (83.4 ± 1.2 vs 78.6 ± 0.5), (all p < 0.01). Also, the 6-year survival of recipients taking statins was 91% compared with 54% in the control group, p < 0.01 [86]. The use of pravastatin therapy has been shown to prolong graft survival in rats [85]. Based on these findings a retrospective study with 502 human subjects confirmed the strong association between the post-operative administration of pravastatin and the improvement of survival, maintenance of graft function, and slowing of the onset of bronchiolitis obliterans [87]. Overall, in post-lung transplant patients, statins appear to improve graft survival and function, as well as, reduce the onset of bronchiolitis obliterans.

11. Conclusion The use of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, or statins, has been evaluated in a variety of pulmonary disorders. However, it is not clear how these results can be extrapolated to current clinical practice due to the limited number of randomized control trials and discrepant data amongst studies. There is evidence suggesting a benefit with the use of statins in patients with chronic obstructive pulmonary disease, whereby these medications may reduce the FEV1 decline, the rate of COPD exacerbations, and respiratory death. However, the results of the recently published STATCOPE trial seem to challenge this data. Statins appear to have minimal benefit in patients with asthma and lung cancer. Mixed results have been obtained in patients with ARDS/ALI and pulmonary hypertension. In conditions like pneumonia, the pre-treatment with statins may limit the evolution to more aggressive types of pneumonia, and decrease mortality. However, there is no clear advantage when administered after the diagnosis is made. While, in patients post-lung transplant, the use of statins is associated with improved graft survival and function, and a decreased incidence of bronchiolitis obliterans. Ongoing, randomized, clinical trials are of the utmost importance in determining whether statins have a role in the prevention and treatment of pulmonary disorders (Table 1). These studies, in addition to existing clinical data, should lay the groundwork for

Table 1 Ongoing clinical trials with statins and in pulmonary conditions. Clinical trial

Intervention

Number of patients

Effect of Rosuvastatin therapy in patients with stable chronic obstructive pulmonary disease (RODEO) PHASE 2 Simvastatin in chronic obstructive pulmonary disease (COPD) PHASE 4 Atorvastatin to treat pulmonary sarcoidosis PHASE 2 Statins for acutely injured lungs from sepsis (SAILS) PHASE 3 Hydroxymethylglutaryl-CoA reductase inhibitors with Simvastatin in acute lung injury to reduce pulmonary dysfunction (HARP-2) PHASE 2 Effect of Simvastatin on pneumonia prognosis in elderly patients PHASE 3 Donor Simvastatin treatment in organ transplantation (SIMVA) PHASE 0 Effect of Atorvastatin on the frequency of ventilator-associated pneumonia in patients with ischemic stroke PHASE 0

Rosuvastatin vs Placebo

140

Simvastatin vs Placebo Atorvastatin

20 96

Rosuvastatin vs Placebo Simvastatin vs Placebo

1000

Simvastatin vs Placebo Simvastatin vs Placebo Atorvastatin vs Placebo

200

540

46 100

future guidelines and recommendations for statin use in these patient populations. Source of funding None. References [1] Pignone M, Phillips C, Mulrow C. Use of lipid lowering drugs for primary prevention of coronary heart disease: meta-analysis of randomised trials. BMJ 2000;321:983e6. [2] Tonkin A, Aylward P, Colquhoun D, Glasziou P, Harris P, MacMahon S, et al. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The long-term intervention with pravastatin in ischemic disease (LIPID) study group. New Eng J Med 1998;339:1349e57. [3] Mihos CG, Santana O. Pleiotropic effects of the HMG-CoA reductase inhibitors. Int J Gen Med 2011;4:261e71. [4] Mihos CG, Salas MJ, Santana O. The pleiotropic effects of the hydroxy-methylglutaryl-CoA reductase inhibitors in cardiovascular disease: a comprehensive review. Cardiol Rev 2010;18:298e304. [5] Mihos CG, Artola RT, Santana O. The pleiotropic effects of the hydroxy-methylglutaryl-CoA reductase inhibitors in rheumatologic disorders: a comprehensive review. Rheumatol Int 2012;32:287e94. [6] Endres M. Statins and stroke. J Cereb Blood Flow Metab 2005;25:1093e110. [7] Li J, Li JJ, He JG, Nan JL, Guo YL, Xiong CM. Atorvastatin decreases C-reactive protein-induced inflammatory response in pulmonary artery smooth muscle cells by inhibiting nuclear factor-kappaB pathway. Cardiovasc Ther 2010;28: 8e14. [8] Altose MD. Approaches to slowing the progression of COPD. Curr Opin Pulm Med 2003;9:125e30. [9] Spurzem JR, Rennard SI. Pathogenesis of COPD. Semin Respir Crit Care Med 2005;26:142e53. [10] Gan WQ, Man SF, Senthilselvan A, Sin DD. Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax 2004;59:574e80. [11] Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, et al. TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775e89. [12] Abboud RT, Vimalanathan S. Pathogenesis of COPD Part I the role of proteaseantiprotease imbalance in emphysema. Int J Tuberc Lung Dis 2008;12:361e7. [13] Sin DD, Man SF. Why are patients with chronic obstructive pulmonary disease at increased risk of cardiovascular diseases? the potential role of systemic inflammation in chronic obstructive pulmonary disease. Circulation 2003;107:1514e9. [14] Barnes PJ, Celli BR. Systemic manifestations and comorbidities of COPD. Eur Respir J 2009;33:1165e85. [15] Hothersall E, McSharry C, Thomson NC. Potential therapeutic role for statins in respiratory disease. Thorax 2006;61:729e34. [16] Lee JH, Lee DS, Kim EK, Choe KH, Oh YM, Shim TS, et al. Simvastatin inhibits cigarette smoking-induced emphysema and pulmonary hypertension in rat lungs. Am J Respir Crit Care Med 2005;172:987e93. [17] Cazzola M, Ciaprini C, Page CP, Matera MG. Targeting systemic inflammation: novel therapies for the treatment of chronic obstructive pulmonary disease. Expert Opin Ther Targets 2007;11:1273e86. [18] Walsh GM. Statins as emerging treatments for asthma and chronic obstructive pulmonary disease. Expert Rev Respir Med 2008;2:329e35. [19] Søyseth V, Brekke PH, Smith P, Omland T. Statin use is associated with reduced mortality in COPD. Eur Respir J 2007;29:279e83. [20] Blamoun AI, Batty GN, DeBari VA, Rashid AO, Sheikh M, Khan MA. Statins may reduce episodes of exacerbation and the requirement for intubation in patients with COPD: evidence from a retrospective cohort study. Int J Clin Pract 2008;62:1373e8. [21] Keddissi JI, Younis WG, Chbeir EA, Daher NN, Dernaika TA, Kinasewitz GT. The use of statins and lung function in current and former smokers. Chest 2007;132:1764e71. [22] Alexeeff SE, Litonjua AA, Sparrow D, Vokonas PS, Schwartz J. Statin use reduces decline in lung function: VA normative aging study. Am J Respir Crit Care Med 2007;176:742e7. [23] Huang CC, Chan WL, Chen YC, Chen TJ, Chou KT, Lin SJ, et al. Statin use and hospitalization in patients with chronic obstructive pulmonary disease: a nationwide population-based cohort study in Taiwan. Clin Ther 2011;33: 1365e70. [24] Undas A, Kaczmarek P, Sladek K, Stepien E, Skucha W, Rzeszutko M, et al. Fibrin clot properties are altered in patients with chronic obstructive pulmonary disease beneficial effects of simvastatin treatment. Thromb Haemost 2009;102:1176e82. [25] Lee TM, Chen CC, Shen HN, Chang NC. Effects of pravastatin on functional capacity in patients with chronic obstructive pulmonary disease and pulmonary hypertension. Clin Sci (Lond) 2009;116:497e505.

R.K. Krishna et al. / Pulmonary Pharmacology & Therapeutics 30 (2015) 134e140 [26] Lee TM, Lin MS, Chang NC. Usefulness of C-reactive protein and interleukin-6 as predictors of outcomes in patients with chronic obstructive pulmonary disease receiving pravastatin. Am J Cardiol 2008;101:530e5. [27] Heart Protection Study Collaborative Group. The effects of cholesterol lowering with simvastatin on cause-specific mortality and on cancer incidence in 20,536 high-risk people: a randomised placebo-controlled trial. BMC Med 2005;3:6. [28] Lahousse L, Loth DW, Joos GF, Hofman A, Leufkens HG, Brusselle GG, et al. Statins, systemic inflammation and risk of death in COPD: the rotterdam study. Pulm Pharmacol Ther 2013;26:212e7. [29] Lawes CM, Thornley S, Young R, Hopkins R, Marshall R, Chan WC, et al. Statin use in COPD patients is associated with a reduction in mortality: a national cohort study. Prim Care Respir J 2012;21:35e40. [30] Criner GJ, Connett JE, Aaron SD, Albert RK, Bailey WC, Casaburi R, et al. The COPD clinical research network and the Canadian Institutes of health Research. Simvastatin for the prevention of exacerbations in moderate-tosevere COPD. N Engl J Med 2014 Jun 5;370(23):2201e10. [31] Greenwood J, Steinman L, Zamvil SS. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol 2006;6: 358e70. [32] Hakamada-Taguchi R, Uehara Y, Kuribayashi K, Numabe A, Saito K, Negoro H, et al. Inhibition of hydroxymethylglutaryl-coenzyme a reductase reduces Th1 development and promotes Th2 development. Circ Res 2003;93:948e56. [33] McKay A, Leung BP, McInnes IB, Thomson NC, Liew FY. A novel antiinflammatory role of simvastatin in a murine model of allergic asthma. J Immunol 2004;172:2903e8. [34] Imamura M, Okunishi K, Ohtsu H, Nakagome K, Harada H, Tanaka R, et al. Pravastatin attenuates allergic airway inflammation by suppressing antigen sensitization, interleukin 17 production and antigen presentation in the lung. Thorax 2009;64:44e9. [35] Menzies D, Nair A, Meldrum KT, Fleming D, Barnes M, Lipworth BJ. Simvastatin does not exhibit therapeutic anti-inflammatory effects in asthma. J Allergy Clin Immunol 2007;119:328e35. [36] Hothersall EJ, Chaudhuri R, McSharry C, Donnelly I, Lafferty J, McMahon AD, et al. Effects of atorvastatin added to inhaled corticosteroids on lung function and sputum cell counts in atopic asthma. Thorax 2008;63:1070e5. [37] Cowan DC, Cowan JO, Palmay R, Williamson A, Taylor DR. Simvastatin in the treatment of asthma: lack of steroid-sparing effect. Thorax 2010;65:891e6. [38] Braganza G, Chaudhuri R, McSharry C, Weir CJ, Donnelly I, Jolly L, et al. Effects of short-term treatment with atorvastatin in smokers with asthmaea randomized controlled trial. BMC Pulm Med 2011;11:11e6. [39] Atorvastatin to Treat Pulmonary Sarcoidosis: A randomized, double-blind, placebo-controlled trial. In: ClinicalTrials.gov, NCT 00279708. [40] Park IH, Kim JY, Jung JI, Han JY. Lovastatin overcomes gefitinib resistance in human non-small cell lung cancer cells with K-Ras mutations. Invest New Drugs 2010;28:791e9. [41] Hanai J, Doro N, Sasaki AT, Kobayashi S, Cantley LC, Seth P, et al. Inhibition of lung cancer growth: ATP citrate lyase knockdown and statin treatment leads to dual blockade of mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)/AKT pathways. J Cell Physiol 2012;227:1709e20. [42] Maksimova E, Yie TA, Rom WN. In vitro mechanisms of lovastatin on lung cancer cell lines as a potential chemopreventive agent. Lung 2008;186:45e54. [43] Yao CJ, Lai GM, Chan CF, Cheng AL, Yang YY, Chuang SE. Dramatic synergistic anticancer effect of clinically achievable doses of lovastatin and troglitazone. Int J Cancer 2006;118:773e9. [44] Khurana V, Bejjanki HR, Caldito G, Owens MW. Statins reduce the risk of lung cancer in humans: a large case-control study of US veterans. Chest 2007;131: 1282e8. [45] Van Gestel YR, Hoeks SE, Sin DD, Hüzeir V, Stam H, Mertens FW, et al. COPD and cancer mortality: the influence of statins. Thorax 2009;64:963e7. [46] Han JY, Lim KY, Yu SY, Yun T, Kim HT, Lee JS. A phase 2 study of irinotecan, cisplatin, and simvastatin for untreated extensive-disease small cell lung cancer. Cancer 2011;117:2178e85. [47] Rhodes CJ, Davidson A, Gibbs JS, Wharton J, Wilkins MR. Therapeutic targets in pulmonary arterial hypertension. Pharmacol Ther 2009;121:69e88. [48] Crosswhite P, Sun Z. Nitric oxide, oxidative stress and inflammation in pulmonary arterial hypertension. J Hypertens 2010;28:201e12. [49] Newman JH, Fanburg BL, Archer SL, Badesch DB, Barst RJ, Garcia JG, et al. National Heart, Lung and Blood Institute/Office of Rare Diseases. Pulmonary arterial hypertension: future directions: report of a national heart, lung and blood institute/office of rare diseases workshop. Circulation 2004;109:2947e52. [50] Oka M, Fagan KA, Jones PL, McMurtry IF. Therapeutic potential of RhoA/Rho kinase inhibitors in pulmonary hypertension. Br J Pharmacol 2008;155: 444e54. [51] Xing XQ, Gan Y, Wu SJ, Chen P, Zhou R, Xiang XD. Statins may ameliorate pulmonary hypertension via RhoA/Rho-kinase signaling pathway. Med Hypotheses 2007;68:1108e13. [52] Girgis RE, Mozammel S, Champion HC, Li D, Peng X, Shimoda L, et al. Regression of chronic hypoxic pulmonary hypertension by simvastatin. Am J Physiol Lung Cell Mol Physiol 2007;292:L1105e10. [53] Taraseviciene-Stewart L, Scerbavicius R, Choe KH, Cool C, Wood K, Tuder RM, et al. Simvastatin causes endothelial cell apoptosis and attenuates severe pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2006;291: 668e76.

139

[54] Hsu HH, Ruan T, Ko WJ, Hsu JY, Chen JS, Lee YC, et al. Effects of simvastatin on pulmonary C-fiber sensitivity in rats with monocrotaline-induced pulmonary hypertension. J Heart Lung Transpl 2011;30:332e40. [55] Liu B, Wang XQ, Yu L, Zhou TF, Wang XM, Liu HM. Simvastatin restores downregulated GATA-6 expression in pulmonary hypertensive rats. Exp Lung Res 2009;35:411e26. [56] Satoh K, Fukumoto Y, Nakano M, Sugimura K, Nawata J, Demachi J, et al. Statin ameliorates hypoxia-induced pulmonary hypertension associated with downregulated stromal cell-derived factor-1. Cardiovasc Res 2009;81:226e34. [57] Carlin CM, Peacock AJ, Welsh DJ. Fluvastatin inhibits hypoxic proliferation and p38 MAPK activity in pulmonary artery fibroblasts. Am J Respir Cell Mol Biol 2007;37:447e56. [58] Gao YF, Zhu XD, Shi DM, Jing ZC, Li L, Ma D, et al. The effects of atorvastatin on pulmonary arterial hypertension and expression of p38, p27, and Jab1 in rats. Int J Mol Med 2010;26:541e7. [59] Xie L, Lin P, Xie H, Xu C. Effects of atorvastatin and losartan on monocrotalineinduced pulmonary artery remodeling in rats. Clin Exp Hypertens 2010;32: 547e54. [60] Laudi S, Trump S, Schmitz V, West J, McMurtry IF, Mutlak H, et al. Serotonin transporter protein in pulmonary hypertensive rats treated with atorvastatin. Am J Physiol Lung Cell Mol Physiol 2007;293:630e8. [61] Ozturk EI, Uma S. Effects of atorvastatin and L-arginine treatments on electrical field stimulation-mediated relaxations in pulmonary arterial rings of monocrotaline-induced pulmonary hypertensive rats. J Cardiovasc Pharmacol 2010;56:498e505. [62] Souza-Costa DC, Figueiredo-Lopes L, Alves-Filho JC, Semprini MC, Gerlach RF, Cunha FQ, et al. Protective effects of atorvastatin in rat models of acute pulmonary embolism: involvement of matrix metalloproteinase-9. Crit Care Med 2007;35:239e45. [63] Wilkins MR, Ali O, Bradlow W, Wharton J, Taegtmeyer A, Rhodes CJ, et al. Simvastatin pulmonary hypertension trial (SiPHT) study group. Simvastatin as a treatment for pulmonary hypertension trial. Am J Respir Crit Care Med 2010;181:1106e13. [64] Kawut SM, Bagiella E, Lederer DJ, Shimbo D, Horn EM, Roberts KE, et al. ASA-STAT Study Group. Randomized clinical trial of aspirin and simvastatin for pulmonary arterial hypertension: ASA-STAT. Circulation 2011;123: 2985e93. [65] Jacobson JR, Barnard JW, Grigoryev DN, Ma SF, Tuder RM, Garcia JG. Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury. Am J Physiol Lung Cell Mol Physiol 2005;288:1026e32. [66] Irish Critical Care Trials Group. Acute lung injury and the acute respiratory distress syndrome in Ireland: a prospective audit of epidemiology and management. Crit Care 2008;12:R30. [67] Kor DJ, Iscimen R, Yilmaz M, Brown MJ, Brown DR, Gajic O. Statin administration did not influence the progression of lung injury or associated organ failures in a cohort of patients with acute lung injury. Intensive Care Med 2009;35:1039e46. [68] Craig TR, Duffy MJ, Shyamsundar M, McDowell C, O'Kane CM, Elborn JS, et al. A randomized clinical trial of hydroxymethylglutaryl- coenzyme a reductase inhibition for acute lung injury (The HARP Study). Am J Respir Crit Care Med 2011;183:620e6. [69] National Heart, Lung, and Blood Institute ARDS Clinical Trials Network, Truwit JD, Bernard GR, Steingrub J, Matthay MA, Liu KD, Albertson TE, et al. Rosuvastatin for sepsis-associated acute respiratory distress syndrome. N Engl J Med 2014 Jun 5;370(23):2191e200.
ndez AB, Karas RH, Alsheikh-Ali AA, Thompson PD. Statins and inter[70] Ferna stitial lung disease: a systematic review of the literature and of food and drug administration adverse event reports. Chest 2008;134:824e30. [71] De Groot RE, Willems LN, Dijkman JH. Interstitial lung disease with pleural effusion caused by simvastatin. J Intern Med 1996;239:361e3. €t-Loheac N, Andre
N, Couturaud F, Chenu E, Quiot JJ, Leroyer C. Hy[72] Liscoe persensitivity pneumonitis in a patient taking pravastatin. Rev Mal Respir 2001;18:426e8. [73] Lantuejoul S, Brambilla E, Brambilla C, Devouassoux G. Statin-induced fibrotic nonspecific interstitial pneumonia. Eur Respir J 2002;19:577e80. [74] Xu JF, Washko GR, Nakahira K, Hatabu H, Patel AS, Fernandez IE, et al. COPDGene Investigators. Statins and pulmonary fibrosis: the potential role of NLRP3 inflammasome activation. Am J Respir Crit Care Med 2012;185: 547e56. [75] Mortensen EM, Coley CM, Singer DE, Marrie TJ, Obrosky DS, Kapoor WN, et al. Causes of death for patients with community-acquired pneumonia: results from the pneumonia patient outcomes research team cohort study. Arch Intern Med 2002;162:1059e64. [76] Kellum JA, Kong L, Fink MP, Weissfeld LA, Yealy DM, Pinsky MR, et al. GenIMS Investigators. Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the genetic and inflammatory markers of sepsis (GenIMS) study. Arch Intern Med 2007;167:1655e63. [77] Van de Garde EM, Hak E, Souverein PC, Hoes AW, van den Bosch JM, Leufkens HG. Statin treatment and reduced risk of pneumonia in patients with diabetes. Thorax 2006;61:957e61. [78] Schlienger RG, Fedson DS, Jick SS, Jick H, Meier CR. Statins and the risk of pneumonia: a population-based, nested case-control study. Pharmacotherapy 2007;27:325e32. [79] Myles PR, Hubbard RB, McKeever TM, Pogson Z, Smith CJ, Gibson JE. Risk of community-acquired pneumonia and the use of statins, ace inhibitors and

140

[80]

[81]

[82]

[83]

R.K. Krishna et al. / Pulmonary Pharmacology & Therapeutics 30 (2015) 134e140 gastric acid suppressants: a population-based case-control study. Pharmacoepidemiol Drug Saf 2009;18:269e75. Mortensen EM, Restrepo MI, Anzueto A, Pugh J. The effect of prior statin use on 30-day mortality for patients hospitalized with community-acquired pneumonia. Respir Res 2005;6:82. Mortensen EM, Pugh MJ, Copeland LA, Restrepo MI, Cornell JE, Anzueto A, et al. Impact of statins and angiotensin-converting enzyme inhibitors on mortality of subjects hospitalised with pneumonia. Eur Respir J 2008;31: 611e7. Mortensen EM, Restrepo MI, Copeland LA, Pugh JA, Anzueto A, Cornell JE, et al. Impact of previous statin and angiotensin II receptor blocker use on mortality in patients hospitalized with sepsis. Pharmacotherapy 2007;27:1619e26. Chalmers JD, Singanayagam A, Murray MP, Hill AT. Prior statin use is associated with improved outcomes in community-acquired pneumonia. Am J Med 2008;121:1002e7.

[84] Kwok CS, Yeong JK, Turner RM, Cavallazzi R, Singh S, Loke YK. Statins and associated risk of pneumonia: a systematic review and meta-analysis of observational studies. Eur J Clin Pharmacol 2012;68:747e55. [85] Papazian L, Roch A, Charles P, Penot-Ragon C, Perrin G, Roulier P, et al. Effect of statin therapy on mortality in patients with ventilator-associated pneumonia: a randomized clinical trial. JAMA 2013;310:1692e700. [86] Johnson BA, Iacono AT, Zeevi A, McCurry KR, Duncan SR. Statin use is associated with improved function and survival of lung allografts. Am J Respir Crit Care Med 2003;167:1271e8. [87] Li Y, Gottlieb J, Ma D, Kuehn C, Strueber M, Welte T, et al. Graft-protective effects of the HMG-CoA reductase inhibitor pravastatin after lung transplantationea propensity score analysis with 23 years of follow-up. Transplantation 2011;92:486e92.