Complement inhibition decreases early fibrogenic events in the lung of septic baboons

Journal of Cellular and Molecular Medicine

Robert Silasi-Mansat²  Hua Zhu²  Constantin Georgescu⁴  Narcis Popescu²  Ravi S. Keshari²  Glenn Peer¹  Cristina Lupu²  Fletcher B. Taylor²  Heloise Anne Pereira³  Gary Kinasewitz¹  John D. Lambris⁵ 

[1] Department of Medicine, Pulmonary and Critical Care Division, Oklahoma University Health Sciences Center, Oklahoma City, OK, USA;Programs in Cardiovascular Biology, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA;Department of Pathology, Oklahoma University Health Sciences Center, Oklahoma City, OK, USA;Programs in Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA;Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

关键词: lung;    organ failure;    sepsis;    complement;    fibrosis;   

DOI  :  10.1111/jcmm.12667

来源: Wiley

【 摘 要 】

Abstract

Acute respiratory distress syndrome (ARDS) induced by severe sepsis can trigger persistent inflammation and fibrosis. We have shown that experimental sepsis in baboons recapitulates ARDS progression in humans, including chronic inflammation and long-lasting fibrosis in the lung. Complement activation products may contribute to the fibroproliferative response, suggesting that complement inhibitors are potential therapeutic agents. We have been suggested that treatment of septic baboons with compstatin, a C3 convertase inhibitor protects against ARDS-induced fibroproliferation. Baboons challenged with 10⁹ cfu/kg (LD50) live E. coli by intravenous infusion were treated or not with compstatin at the time of challenge or 5 hrs thereafter. Changes in the fibroproliferative response at 24 hrs post-challenge were analysed at both transcript and protein levels. Gene expression analysis showed that sepsis induced fibrotic responses in the lung as early as 24 hrs post-bacterial challenge. Immunochemical and biochemical analysis revealed enhanced collagen synthesis, induction of profibrotic factors and increased cell recruitment and proliferation. Specific inhibition of complement with compstatin down-regulated sepsis-induced fibrosis genes, including transforming growth factor-beta (TGF-β), connective tissue growth factor (CTGF), tissue inhibitor of metalloproteinase 1 (TIMP1), various collagens and chemokines responsible for fibrocyte recruitment (e.g. chemokine (C-C motif) ligand 2 (CCL2) and 12 (CCL12)). Compstatin decreased the accumulation of myofibroblasts and proliferating cells, reduced the production of fibrosis mediators (TGF-β, phospho-Smad-2 and CTGF) and inhibited collagen deposition. Our data demonstrate that complement inhibition effectively attenuates collagen deposition and fibrotic responses in the lung after severe sepsis. Inhibiting complement could prove an attractive strategy for preventing sepsis-induced fibrosis of the lung.

【 授权许可】

CC BY   
© 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.