Sepsis is a complex clinical syndrome of systemic inflammation and dysregulation of the immune system in response to infection [1]. This dynamic systemic illness spans a continuum of severity ranging from sepsis to severe sepsis to septic shock, the most extreme complication of sepsis [2]. Septic shock is a hyperdynamic state that occurs when widespread infection has led to profound immune-mediated systemic vasodilation with hypotension, endothelial dysfunction and maldistribution of blood flow with cellular hypoxia leading to diffuse tissue injury and multi-organ failure [3-8].
The endothelium plays a pivotal role in the pathogenesis of sepsis and septic shock. It is not merely a barrier between intravascular and interstitial spaces, but rather the endothelium is a complex and highly metabolic organ involved in a myriad of physiological functions, including maintaining vascular tone, regulating leukocyte trafficking and participating in the coagulation cascade [9,10]. Sepsis causes diffuse endothelial damage, which affects these physiological processes, thereby resulting in loss of vascular tone, inflammation and coagulopathy that form the hallmarks of this systemic illness [11,12].
The Renin-Angiotensin-Aldosterone System (RAAS) is activated in critical illness and plays a crucial role in the initiation and maintenance of vascular inflammation [13,14]. Activation of RAAS during sepsis has been shown to promote inflammation and endothelial injury by release of pro-oxidants and potent vasopressors, leading to microcirculatory perfusion deficits and the development of organ dysfunction [14-18].
There is increasing evidence from experimental and clinical studies that Angiotensin- Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs) possess immunomodulating effects through blockade of the RAAS, thereby reducing inflammatory cytokines and improving endothelial function [19-21]. Several recent studies have demonstrated that pre-hospitalization use of ACE inhibitors and ARBs are associated with improved clinical outcomes in patients with pneumonia, chronic obstructive lung disease and sepsis [22-24]. However, conflicting data has subsequently emerged regarding pre-hospital use of ARBs and risk of sepsis from the TRANSCEND and PRoFESS studies that showed that the use of telmisartan (ARB) was associated with an increased risk of sepsis related adverse events [25,26]. More recently another study raised concern with prior use of ACE inhibitors and increased sepsis related mortality but not for ARBs [27]. Thus overall data regarding blockade of the RAAS system, particularly of angiotensin 11, and outcomes with sepsis remain unclear. More specifically the use of ARBs and ACE inhibitors and outcomes in septic shock has not been studied to our knowledge.
In the present study, we sought to investigate the association of pre-hospitalization use of ACE inhibitors and ARBs on mortality in a population of septic shock patients admitted to our medical Intensive Care Unit (ICU).

Henry Ford Hospital (Detroit, MI) is a tertiary care center with a 68-bed ICU. Septic shock is one of the leading causes of ICU admission in our ICUs. We retrospectively reviewed a total of 248 consecutive patients admitted to our ICU with septic shock between January 2011 and April 2013. Patients with septic shock were identified by a computer search of the diagnostic codes - according to the International Classification of Disease, 9th Revision - of all discharge diagnoses. The medical records of all of the patients with a diagnostic code for septic shock were then manually reviewed for verification by the investigating physicians. This study was conducted in accordance with the amended Declaration of Helsinki. The Institutional Review Board of Henry Ford Hospital approved the study. Baseline demographic, clinical and echocardiographic data were obtained at the time of ICU admission by reviewing the electronic medical records. Clinical data was obtained within 24 hours of ICU admission. Echocardiographic data was obtained from the earliest echocardiogram obtained during the ICU stay.
Follow-up data was obtained through a review of medical records and the Social Security Death Index.
Patients were included for analysis in this investigation only if they met criteria for septic shock, defined as known or suspected infection with 2 or more signs of systemic inflammatory response syndrome, organ dysfunction and hypotension, defined as a systolic blood pressure less than 90 mm Hg or mean arterial pressure less than 65 mm Hg after a 30 mL/kg fluid bolus or requiring vasopressor therapy. Excluded were patients with suspected cardiogenic shock on the basis of reduced mixed central venous oxygen saturation, as well as myocardial ischemia as evidenced by wall motion abnormalities on echocardiogram, severe mitral or aortic valve disease, preexisting severe impairment in left ventricular ejection fraction and patients with poor echocardiographic image quality. Univariate analysis was performed using independent t-tests for continuous variables, and using chi-square tests for categorical variables. P-values less than 0.05 were considered statistically significant. All analyses were performed using SAS version 9.2 (SAS Institute Inc, Cary, NC).
Medication data were obtained via chart review using the electronic medical record. Patients were included in the medication group if they had recent documentation or prescription for the given medication within a month (or within 90 days with refills) of hospitalization admission. Medications classified as ACE inhibitors were lisinopril, benazepril, captopril, enalapril, fosinopril, moexipril, quinapril and ramipril. Medications classified as angiotensin II receptor blockers (ARBs) included losartan, valsartan, candesartan, irbesartan and telmisartan. Due to the small number of patients on ARB, the ACE inhibitor and ARB data were combined into 1 variable.

Out of 300 patients who were admitted to the ICU in shock, 248 patients met our criteria for septic shock and were subsequently analyzed. The mean +/- standard deviation age was 64.9 +/- 18 years and 126 patients (51%) were men. There were a total of 90 patients (36%) in the ACE inhibitor/ARB group. Table 1 shows the demographic and comorbid condition relationship with use of ACE inhibitor or ARB. The ACE inhibitor/ARB group was more likely to have a higher body mass index and hypertension. Other comorbidities were similar between both groups.
The ACE inhibitor/ARB group was found to have significantly lower heart rates (95.8 bpm vs 102.3 bpm, p < 0.05), higher mean arterial pressures (80 mm Hg vs 74 mm Hg, p < 0.05), higher serum potassium levels (4.3 mEq/L vs 4.0 mEq/L, p < 0.05) and lower urine outputs (522 ml vs 708 ml per initial 24 hours, p < 0.05) compared to the non-ACE inhibitor/ARB group.
Furthermore, the ACE inhibitor/ARB group had a nonsignificant trend towards lower respiratory rates, white blood cell counts, lactate levels and APACHE II scores (Table 2).
The ACE inhibitor/ARB group also had higher left ventricular systolic diameters (1.26 cm vs 1.17 cm, p < 0.05) and left ventricular posterior wall diameters (1.18 cm vs 1.07 cm, p < 0.05); however, there were no other statistically significant echocardiographic differences between both groups (Table 3). In-hospital and 90-day mortality was significantly less in the ACE inhibitor/ARB group compared to the non-ACE inhibitor/ARB group (20% vs 31.7%, p < 0.05) and (25.6% vs 38%, p < 0.05), respectively (Figure 1).

In the present study, we found that prior outpatient use of ACE inhibitors and ARBs in septic shock patients was associated with hemodynamic benefits and improved clinical parameters. The  hemodynamic derangements were significantly less pronounced in patients with pre-hospital ACE inhibitor and ARB use, with lower mean heart rates and higher mean arterial pressures. There was also a trend towards lower respiratory rates, white blood cell counts, lactate levels and APACHE II scores suggesting a less pronounced inflammatory response among septic shock patients in the ACE inhibitor/ARB group. However, pre-hospital use of ACE inhibitors and ARBs were significantly associated with less urine output and higher serum potassium levels, suggesting greater renal dysfunction in this group. Most strikingly, however, our study revealed decrease in-hospital and 90-day mortality among septic shock patients with pre-hospitalization use of ACE inhibitors and ARBs.
Our findings are congruent with those of several recent studies demonstrating improved clinical outcomes in patients with infectious and inflammatory conditions. Recent clinical studies have demonstrated that prior use of ACE inhibitors is associated with reduction in the incidence of pneumonia [22,28-30]. A retrospective study of patients admitted with communityacquired pneumonia demonstrated decreased 30-day mortality among patients who were on ACE inhibitors versus those that were not on ACE inhibitors prior to hospitalization [31]. In another large retrospective study of 11,212 patients greater than 65 years of age hospitalized with acute exacerbation of chronic obstructive pulmonary disease, Mortenson, et al. found that use of ACE inhibitors and ARBs before hospitalization was significantly associated with decreased 90-day mortality [23]. In another recent study of obese trauma patients, pre-hospitalization use of ACE inhibitors and ARBs was found to be significantly associated with improved immune regulation and decreased multiple organ failure scores [32].

However, our study is the first to evaluate the impact prehospitalization use of RAAS blockade therapy on short- and long-term mortality in critically ill patients with septic shock. Our findings suggest that modulation of the RAAS pathway might represent a novel therapeutic target in critically ill patients in septic shock. However, the potential benefits of acute RAAS blockade need to be weighed against possible worsened renal function based on the observed trend we found in our study. In our study, the echocardiographic parameters between both groups were similar, except for left ventricle end systolic diameter (LVESD) and left ventricle posterior wall diameter (LVPWD). Both study cohorts had reduced mean LVESD, as expected with increased ionotropy in the high output state of septic shock. However, the ACE inhibitor/ARB group had a higher LVESD and LVPWD, likely due to preexisting left ventricular remodeling from chronic hypertension for which the medications were indicated. We do not suspect that the improvements in clinical outcomes in patients with ACE inhibitors/ARBs are explained by these echocardiographic differences. Furthermore, while it was observed that approximately a quarter of patients in both cohorts had a pre-existing diagnosis of congestive heart failure, this referred mostly to patients with pre-existing heart failure with preserved ejection fraction (HFpEF) and, as previously mentioned, we excluded patients with severely reduced baseline LV systolic function of less than 35%.
The RAAS has been shown to induce an inflammatory response by mediating key parts of the inflammatory process [14,33- 37]. In patients with rheumatoid arthritis and systemic lupus erythematosus, ACE levels have been shown to be upregulated in the synovial tissue causing elevation of angiotensin II levels in the inflamed joints [38-40]. Early angiotensin II levels have been shown to correlate with the Sequential Organ Failure Assessment (SOFA) score, extent of organ dysfunction and sepsis mortality [15].

The hemodynamic benefits of ACE inhibitors in the management of heart failure is well established [41-43]. Existing data has shown that prolonged ACE inhibitor use exerts immunomodulating effects in patients with chronic heart failure, resulting in reduction of pro-inflammatory mediators including tumor necrosis factor-α and interleukin-6, reduction in endothelial adhesion molecule concentrations, improvement in cyclooxygenase-dependent vasoactive factors and improvement in endothelial function [44-48]. Similarly, recent experimental and clinical studies have demonstrated that ACE inhibitors reduce pro-inflammatory cytokines, reduce endothelial-derived adhesion molecules, improve endothelial function and preserve microcirculatory homeostasis during sepsis and septic shock [17-20]. Use of ACE inhibitors in animal studies have been shown to decrease bacterial translocation in gut derived sepsis [49], block lipopolysaccharide-induced inflammatory response, protect against acute lung injury [21], prevent the development of pulmonary arterial hypertension and acute respiratory distress syndrome [50] and reduce lung inflammation during barotrauma [51].
With increasing evidence of the reduced pro-inflammatory effects of RAAS with use of ACE inhibitors/ARBs in experimental studies and accumulating clinical studies demonstrating improvement in outcomes of patients with infectious and inflammatory conditions, there is currently a growing interest to investigate the potential therapeutic benefits of the RAAS blockade in various models of acute and chronic inflammatory conditions.

There are several limitations to our study. The retrospective nature of the study, the limited sample size and that it was performed at a single center overall limits the generalizability of our results. Furthermore, while we verified that patients included in the ACE inhibitor/ARB group had been prescribed their medication regimen, an exact measure of patient compliance was not definitive, and therefore, any nonadherence to therapy would have introduced a degree of bias to our study. While our study provides insight into the potential impact of ACE inhibitors/ ARBs on clinical outcomes in patients with septic shock, it is also important to point out that our study focused solely on the prehospitalization use of these medications. Therefore, whether or not RAAS blockade with the use of ACE inhibitors/ARBs during septic shock is associated with improvement in clinical outcomes cannot be concluded from our study, and prospective, randomized clinical trials are required to establish any causal association.

Conclusion

Blockade of the RAAS pathway by ACE inhibitors and ARBs prior to ICU admission is associated with improved outcomes in patients with septic shock. Improvement in clinical outcomes was not explained by laboratory or echocardiographic differences. Our study provides further support for the possible immunomodulating benefits of ACE inhibitors and ARBs; however, large prospective clinical studies are needed to confirm these findings.

Acknowledgements

Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-forprofit sectors. We thank our librarian Stephanie Stebens for her assistance with manuscript editing and formatting.

Conflicts of interest
None.

Abbreviations

Angiotensin-Converting Enzyme (ACE), Angiotensin Receptor Blocker (ARB), Intensive Care Unit (ICU), Acute Physiology And Chronic Health Evaluation (APACHE II); Renin-Angiotensin-Aldosterone System (RAAS; LVEDD, Left Ventricle End-Diastolic Dimension; LVESD, Left Ventricle End-Systolic Dimension; IVSD, Interventricular Septal Diameter; LVPWD, Left Ventricle Posterior Wall Diameter; LVEF, Left Ventricle Ejection Fraction; LVSI, Left Ventricle Stroke Index; LV CO, Left Ventricle Cardiac Output; LV CI, Left Ventricle Cardiac Index; MV, Mitral Valve; RA, Right Atrium; RVSP, Right Ventricle Systolic Pressure; RV, Right Ventricle; RVD, Right Ventricle Diameter; TAPSE, Triscupsid Annular Plane Systolic Excursion; MR, Mitral Regurgitation; TR, Tricuspid Regurgitation; AI, Aortic Insufficiency; IVC, Inferior Vena Cava

1. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810.
2. Gustot T. Multiple organ failure in sepsis: prognosis and role of systemic inflammatory response. Curr Opin Crit Care. 2011;17(2):153-159.
3. Boisrame-Helms J, Kremer H, Schini-Kerth V, Meziani F. Endothelial dysfunction in sepsis. Curr Vasc Pharmacol. 2013;11(2):150-160.
4. Vallet B. Bench-to-bedside review: endothelial cell dysfunction in severe sepsis: a role in organ dysfunction? Crit Care. 2003;7(2):130-138.
5. Trzeciak S, Dellinger RP, Parrillo JE, et al. Early microcirculatory perfusion derangements in patients with severe sepsis and septic shock: relationship to hemodynamics, oxygen transport, and survival. Ann Emerg Med. 2007;49(1):88-98.
6. Ellis CG, Bateman RM, Sharpe MD, Sibbald WJ, Gill R. Effect of a maldistribution of microvascular blood flow on capillary O(2) extraction in sepsis. Am J Physiol Heart Circ Physiol. 2002;282(1):H156-H164.
7. De Backer D, Creteur J, Preiser JC, Dubois MJ, Vincent JL. Microvascular blood flow is altered in patients with sepsis. Am J Respir Crit Care Med. 2002;166(1):98-104.
8. Chierego M, Verdant C, De Backer D. Microcirculatory alterations in critically ill patients. Minerva Anestesiol. 2006;72(4):199-205.
9. Michiels C. Endothelial cell functions. J Cell Physiol. 2003;196(3):430-443.
10. De Caterina R, Massaro M, Libby P. Endothelial functions and dysfunctions. In: de Caterina R, Libby P, eds. Endothelial Dysfunctions in Vascular Disease. Oxford: Blackwell; 2007:3-25.
11. Johansen ME, Johansson PI, Ostrowski SR, et al. Profound endothelial damage predicts impending organ failure and death in sepsis. Semin Thromb Hemost. 2015;41(1):16-25.
12. Szabo C, Goldstein B. Endothelial dysfunction as predictor of mortality in sepsis. Crit Care Med. 2011;39(4):878-879.
13. Fyhrquist F, Saijonmaa O. Renin-angiotensin system revisited. J Intern Med. 2008;264(3):224-236.
14. Suzuki Y, Ruiz-Ortega M, Lorenzo O, Ruperez M, Esteban V, Egido J. Inflammation and angiotensin II. Int J Biochem Cell Biol. 2003;35(6):881-900.
15. Doerschug KC, Delsing AS, Schmidt GA, Ashare A. Renin-angiotensin system activation correlates with microvascular dysfunction in a prospective cohort study of clinical sepsis. Crit Care. 2010;14(1):R24.
16. Pacurari M, Kafoury R, Tchounwou PB, Ndebele K. The renin-angiotensinaldosterone system in vascular inflammation and remodeling. Int J Inflam. 2014;2014:689360.
17. Wiel E, Pu Q, Leclerc J, et al. Effects of the angiotensin-converting enzyme inhibitor perindopril on endothelial injury and hemostasis in rabbit endotoxic shock. Intensive Care Med. 2004;30(8):1652-1659.
18. Lund DD, Brooks RM, Faraci FM, Heistad DD. Role of angiotensin II in endothelial dysfunction induced by lipopolysaccharide in mice. Am J Physiol Heart Circ Physiol. 2007;293(6):H3726-H3731.
19. Dandona P, Kumar V, Aljada A, et al. Angiotensin II receptor blocker valsartan suppresses reactive oxygen species generation in leukocytes, nuclear factor-kappa B, in mononuclear cells of normal subjects: evidence of an antiinflammatory action. J Clin Endocrinol Metab. 2003;88(9):4496-4501.
20. Boldt J, Papsdorf M, Kumle B, Piper S, Hempelmann G. Influence of angiotensin-converting enzyme inhibitor enalaprilat on endothelial-derived substances in the critically ill. Crit Care Med. 1998;26(10):1663-1670.
21. Hagiwara S, Iwasaka H, Matumoto S, Hidaka S, Noguchi T. Effects of an angiotensin-converting enzyme inhibitor on the inflammatory response in in vivo and in vitro models. Crit Care Med. 2009;37(2):626-633.
22. Mortensen EM, Nakashima B, Cornell J, et al. Population-based study of statins, angiotensin II receptor blockers, and angiotensin-converting enzyme inhibitors on pneumonia-related outcomes. Clin Infect Dis. 2012;55(11):1466-1473.
23. Mortensen EM, Copeland LA, Pugh MJ, et al. Impact of statins and ACE inhibitors on mortality after COPD exacerbations. Respir Res. 2009;10(1):45.
24. Mortensen EM, Restrepo MI, Copeland LA, et al. Impact of previous statin and angiotensin II receptor blocker use on mortality in patients hospitalized with sepsis. Pharmacotherapy. 2007;27(12):1619-1626.
25. Telmisartan Randomised AssessmeNt Study in ACE iNtolerant Subjects with Cardiovascular Disease Investigators, Yusuf S, Teo K, et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet. 2008;372(9644):1174-1183.
26. Diener HC, Sacco RL, Yusuf S, et al. Effects of aspirin plus extendedrelease dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischaemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial: a double-blind, active and placebo-controlled study. Lancet Neurol.
2008;7(10):875-884.
27. Dial S, Nessim SJ, Kezouh A, Benisty J, Suissa S. Antihypertensive agents acting on the renin-angiotensin system and the risk of sepsis. Br J Clin Pharmacol. 2014;78(5):1151-1158.
28. Etminan M, Zhang B, Fitzgerald M, Brophy JM. Do angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers decrease the risk of hospitalization secondary to community-acquired pneumonia? A nested case-control study. Pharmacotherapy. 2006;26(4):479-482.
29. van de Garde EM, Souverein PC, Hak E, Deneer VH, van den Bosch JM, Leufkens HG. Angiotensin-converting enzyme inhibitor use and protection against pneumonia in patients with diabetes. J Hypertens. 2007;25(1):235-239.
30. Mortensen EM, Pugh MJ, Copeland LA, et al. Impact of statins and angiotensin-converting enzyme inhibitors on mortality of subjects hospitalised with pneumonia. Eur Respir J. 2008;31(3):611-617.
31. Mortensen EM, Restrepo MI, Anzueto A, Pugh J. The impact of prior outpatient ACE inhibitor use on 30-day mortality for patients hospitalized with community-acquired pneumonia. BMC Pulm Med. 2005;5(1):12.
32. Winfield RD, Southard RE, Turnbull IR, et al. Angiotensin inhibition is associated with preservation of T-cell and monocyte function and decreases multiple organ failure in obese trauma patients. J Am Coll Surg. 2015;221(2):486-494.
33. Bucher M, Ittner KP, Hobbhahn J, Taeger K, Kurtz A. Downregulation of angiotensin II type 1 receptors during sepsis. Hypertension. 2001;38(2):177-182.
34. Bucher M, Hobbhahn J, Kurtz A. Nitric oxide-dependent down-regulation of angiotensin II type 2 receptors during experimental sepsis. Crit Care Med. 2001;29(9):1750-1755.
35. Alvarez A, Cerda-Nicolas M, Naim Abu Nabah Y, et al. Direct evidence of leukocyte adhesion in arterioles by angiotensin II. Blood. 2004;104(2):402-408.
36. Benigni A, Cassis P, Remuzzi G. Angiotensin II revisited: new roles in inflammation, immunology and aging. EMBO Mol Med. 2010;2(7):247-257.
37. Mateo T, Abu Nabah YN, Abu Taha M, et al. Angiotensin II-induced mononuclear leukocyte interactions with arteriolar and venular endothelium are mediated by the release of different CC chemokines. J Immunol. 2006;176(9):5577-5586.
38. Walsh DA, Catravas J, Wharton J. Angiotensin converting enzyme in human synovium: increased stromal [(125)I]351A binding in rheumatoid arthritis. Ann Rheum Dis. 2000;59(2):125-131.
39. Samoriadova OS, Zharova EA, Masenko VP, Balabanova RM, Vil'chinskaia M, Nasonov EL. [The renin-angiotensin-aldosterone system and arterial hypertension in patients with rheumatoid arthritis]. Klin Med (Mosk). 1991;69(2):69-71.
40. Shilkina NP, Stoliarova SA, Iunonin IE, Driazhenkova IV. [Neurohumoral regulation of blood pressure in rheumatic patients]. Ter Arkh. 2009;81(6):37-41.
41. Ader R, Chatterjee K, Ports T, Brundage B, Hiramatsu B, Parmley W. Immediate and sustained hemodynamic and clinical improvement in chronic heart failure by an oral angiotensin-converting enzyme inhibitor. Circulation. 1980;61(5):931-937.
42. LeJemtel TH, Keung E, Frishman WH, Ribner HS, Sonnenblick EH. Hemodynamic effects of captopril in patients with severe chronic heart failure. Am J Cardiol. 1982;49(6):1484-1488.
43. Khalil ME, Basher AW, Brown EJ Jr., Alhaddad IA. A remarkable medical story: benefits of angiotensin-converting enzyme inhibitors in cardiac patients. J Am Coll Cardiol. 2001;37(7):1757-1764.
44. Damas JK, Gullestad L, Aukrust P. Cytokines as new treatment targets in chronic heart failure. Curr Control Trials Cardiovasc Med. 2001;2(6):271-277.
45. Aukrust P, Damas JK, Gullestad L. Immunomodulating therapy: new treatment modality in congestive heart failure. Congest Heart Fail. 2003;9(2):64-69.
46. Schartl M, Bocksch WG, Dreysse S, Beckmann S, Franke O, Hunten U. Remodeling of myocardium and arteries by chronic angiotensin converting enzyme inhibition in hypertensive patients. J Hypertens Suppl. 1994;12(4):S37-S42.
47. Mancini GB, Henry GC, Macaya C, et al. Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease. The TREND (Trial on Reversing ENdothelial Dysfunction) Study. Circulation. 1996;94(3):258-265.
48. Kohlstedt K, Busse R, Fleming I. Signaling via the angiotensin-converting enzyme enhances the expression of cyclooxygenase-2 in endothelial cells. Hypertension. 2005;45(1):126-132.
49. Giannelli V, Di Gregorio V, Iebba V, et al. Microbiota and the gut-liver axis: bacterial translocation, inflammation and infection in cirrhosis. World J Gastroenterol. 2014;20(45):16795-16810.
50. Liu H, Zhao J. An experimental study of therapeutic effect of ACEI on chemicalinduced ARDS in rats. Zhonghua Yu Fang Yi Xue Za Zhi. 2002;36(2):93-96.
51. Marshall RP, Gohlke P, Chambers RC, et al. Angiotensin II and the fibroproliferative response to acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2004;286(1):L156-L164.