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

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 10(9) 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.

• Authors: Robert Silasi-Mansat, Hua Zhu, Constantin Georgescu, Narcis Popescu, Ravi S Keshari, Glenn Peer, Cristina Lupu, Fletcher B Taylor, Heloise Anne Pereira, Gary Kinasewitz, John D Lambris, Florea Lupu
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 19 Issue 11 Pg. 2549-63 (Nov 2015) ISSN: 1582-4934 [Electronic] England
• PMID: 26337158 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Chemical References

• Complement Inactivating Agents
• Peptides, Cyclic
• compstatin

Topics

• Animals
• Bacteremia (drug therapy, immunology, pathology)
• Complement Activation (drug effects)
• Complement Inactivating Agents (therapeutic use)
• Escherichia coli Infections (drug therapy, immunology, physiopathology)
• Fibrosis
• Gene Expression Regulation (drug effects)
• Lung (pathology)
• Peptides, Cyclic (therapeutic use)
• Respiratory Distress Syndrome (drug therapy, immunology, pathology)