Simvastatin decreases the level of heparin-binding protein in patients with acute lung injury

BMC Pulmonary Medicine

Karim Dib³  Heiko Herwald²  Murali Shyamsundar¹  Thelma R Craig¹  Cecilia M O’Kane³  Daniel F McAuley³ 

[1]Regional Intensive Care Unit, Royal Victoria Hospital, Belfast, Northern Ireland, UK

[2]Department of Clinical Sciences, Division of Infection Medicine, University of Lund, Lund, Sweden

[3]Centre for Infection and Immunity, Queen’s University of Belfast, Belfast, United Kingdom

关键词: Neutrophils;    Inflammation;    Heparin-binding protein;    Simvastatin;    Acute lung injury;   

Others  :  1109760
DOI  :  10.1186/1471-2466-13-47

 received in 2013-02-01, accepted in 2013-07-05,  发布年份 2013

【 摘 要 】

Background

Heparin-binding protein is released by neutrophils during inflammation and disrupts the integrity of the alveolar and capillary endothelial barrier implicated in the development of acute lung injury and systemic organ failure. We sought to investigate whether oral administration of simvastatin to patients with acute lung injury reduces plasma heparin-binding protein levels and improves intensive care unit outcome.

Methods

Blood samples were collected from patients with acute lung injury with 48 h of onset of acute lung injury (day 0), day 3, and day 7. Patients were given placebo or 80 mg simvastatin for up to 14 days. Plasma heparin-binding protein levels from patients with acute lung injury and healthy volunteers were measured by ELISA.

Results

Levels of plasma heparin-binding protein were significantly higher in patients with acute lung injury than healthy volunteers on day 0 (p = 0.011). Simvastatin 80 mg administered enterally for 14 days reduced plasma level of heparin-binding protein in patients. Reduced heparin-binding protein was associated with improved intensive care unit survival.

Conclusions

A reduction in heparin-binding protein with simvastatin is a potential mechanism by which the statin may modify outcome from acute lung injury.

Trial registration

Current controlled trials: ISRCTN70127774

【 授权许可】

   
2013 McAuley et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Tsushima K, King LS, Aggarwal NR, De Gorordo A, D’Alessio FR, Kubo K: Acute lung injury review. Inter Med 2009, 48(9):621-630.
• [2]Sinclair DG, Braude S, Haslam PL, Evans TW: Pulmonary permeability in patients with severe lung injury. Clinical correlates and natural history. Chest 1994, 106(2):535-539.
• [3]Steinberg KP, Milberg JA, Martin TR, Maunder RJ, Cockrill BA, Hudson CD: Evolution of bronchoalveolar cell populations in the adult respiratory distress syndrome. Am J Respir Crit Care Med 1994, 150(1):113-122.
• [4]Gautam N, Olofsson AM, Herwald H, Iversen LF, Lundgren-Akerlund E, Hedqvist P, Arfors K-E, Flodgaard H, Lindbom L: Heparin-binding protein (HBP/CAP37): A missing link in neutrophil-evoked alteration of vascular permeability. Nature Med 2001, 7(10):1123-1127.
• [5]Tapper H, Karlsson A, Morgelin M, Flodgaard H, Herwald H: Secretion of heparin-binding protein from human neutrophils is determined by its localization in azurophilic granules and secretory vesicles. Blood 2002, 99(5):1785-1793.
• [6]Shafer WM, Martin LE, Spitznagel JK: Cationic antimicrobial proteins isolated from human neutrophil granulocytes in the presence of diisopropyl fluorophosphates. Infect Immun 1984, 45(1):29-35.
• [7]Soehnlein O, Zernecke A, Eriksson EE, Gigliotti Rothfuchs A, Pham CT, Herwald H, Bidzhekov K, Rottenberg ME, Weber C, Lindbom L: Neutrophil products pave the way for inflammatory monocytes. Blood 2008, 112(4):1461-1471.
• [8]Soehnlein O, Kai-Larsen Y, Frithiof R, Sorensen OE, Kenne E, Scharffetter-Kochanek K, Eriksson EE, Herwald H, Agerberth B, Lindbom L: Neutrophil primary granule proteins HBP and HNP1-3 boost bacterial phagocytosis by human and murine macrophages. J Clin Invest 2008, 118(10):3491-3502.
• [9]Herwald H, Cramer H, Morgelin M, Russell W, Sollenberg U, Norrby-Teglung A, Flodgaard H, Lindbom L, Björck L: M protein, a classical bacterial virulence determinant, forms complexes with fibrinogen that induce vascular leakage. Cell 2004, 116(February 6):367-379.
• [10]Fessler MB, Young SK, Jeyaseelan S, Lieber JG, Arndt PG, Nick JA, Worthen GS: A role for hydroxyl-methylglutaryl coenzyme a reductase in pulmonary inflammation and host defense. Am J Respir Crit Care Med 2005, 171(6):606-615.
• [11]Jacobson JR, Barnard JW, Grigoryev DN, 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(6):L1026-L1032.
• [12]Steiner S, Speidl WS, Pleiner J, Seidinger D, Zorn G, Kaun C, Wojta J, Huber K, Minar E, Wolzt M, Kopp CW: Simvastatin blunts endotoxin-induced tissue factor in vivo. Circulation 2005, 111(14):1842-1846.
• [13]Shyamsundar M, Scott TW, O’Kane CM, Craig TR, Brown V, Thickett DR, Matthay MA, Taggart CC, Backman JT, Elborn JS, McAuley DF: Simvastatin decreases lipopolysaccharide-induced pulmonary inflammation in healthy volunteers. Am J Respir Crit Care Med 2009, 179:1107-1114.
• [14]Craig TR, Duffy MJ, Shyamsundar M, McDowell C, McLaughlin B, Elborn JS, McAuley DF: A randomized clinical trial of hydroxymethylglutaryl-coenzyme A reductase inhibition for acute lung injury (The HARP study). Am J Respir Crit Care Med 2011, 183:620-626.
• [15]Grommes J, Vijayan S, Drechsler M, Hartwig H, Mörgelin M, Dembinski R, Jacobs M, Koeppel TA, Binnebösel M, Weber C, Soehnlein O: Simvastatin reduces endotoxin-induced acute lung injury by decreasing neutrophil recruitment and radical formation. PLoS One 2012, 7(6):e38917.
• [16]Linder A, Akesson P, Inghammar M, Treutiger C-J, Linnér A, Sundén-Cullberg J: Elevated plasma levels of heparin-binding protein in intensive care unit patients with severe sepsis and septic shock. Crit Care 2012, 16:R90.
• [17]Chew MS, Linder A, Santen S, Ersson A, Herwald H, Thorlacius H: Increased plasma levels of heparin-binding protein in patients with shock: a prospective, cohort study. Inflamm Res 2012, 61(4):375-379.
• [18]McAuley DF, Laffey JG, O’Kane CM, Coss M, Perkins GD, Murphy L, McNally C, Crealey G, Stevenson M, HARP investigators; Irish Critical Care Trials Group: Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction (HARP-2) trial: study protocol for a randomized controlled trial. Trials 2012, 13:170. BioMed Central Full Text
• [19]Sengelov H, Kjeldsen L, Diamond MS, Springer TA, Borregaard N: Subcellular localization and dynamics of Mac-1 (alpha m beta 2) in human neutrophils. J Clin Invest 1993, 92:1467-1476.
• [20]Diamond MS, Springer TA: A subpopulation of Mac-1 (CD11b/CD18) molecules mediates neutrophil adhesion to ICAM-1 and fibrinogen. J Cell Biol 1993, 120:545-556.
• [21]Weitz-Schmidt G, Welzenbach K, Brinkmann V, Kamata T, Kallen J, Bruns C, Cottens S, Takada Y, Hommel U: Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nature Med 2001, 7:687-692.
• [22]Zhang S, Rahman M, Zhang S, Qi Z, Herwald H, Thorlacius H: Simvastatin regulates CXC chemokine formation in streptococcal M1 protein-induced neutrophil infiltration in the lung. Am J Physiol Lung Cell Mol Physiol 2011, 300:L930-939.