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Complement inhibition decreases the fibrotic response in septic baboons
Author(s) -
Lupu Florea,
Zhu Hua,
SilasiMansat Robert,
Peer Glenn,
Popescu Narcis,
Magotti Paola,
Lupu Cristina,
Taylor Fletcher B.,
Kinasewitz Gary T.,
Lambris John D.
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.114.7
Subject(s) - fibrosis , ctgf , timp1 , pulmonary fibrosis , sepsis , inflammation , fibrocyte , immunology , myofibroblast , chemokine , medicine , cancer research , pathology , biology , growth factor , gene expression , gene , biochemistry , receptor
Pathogenesis of pulmonary fibrosis ‐ an important complication of lung infection and inflammation ‐ is still unclear. Here we used a baboon model to determine whether E. coli sepsis could augment lung fibrosis and to characterize the effects of complement inhibition on fibrosis‐specific pathways. Microarray gene expression analysis showed that sepsis augmented fibrotic responses in the lung as early as 24 hours post challenge. Immunocytochemical and biochemical analysis revealed enhanced staining for procollagen 3, induction of profibrotic factors and increased recruitment and proliferation of macrophages and fibroblasts. Complement inhibition using compstatin downregulated sepsis‐induced fibrosis genes, including TGFb, CTGF, TIMP1, several collagen genes and chemokines responsible for fibrocyte recruitment, such as CCL2 and CCL12. Compstatin treatment also decreased the accumulation of α‐actin‐positive myofibroblasts, as well as proliferating cells positive for PCNA and phosphoMAPK p44/p42, in addition to reducing fibrosis mediators (TGFb, Phospho Smad‐2 and CTGF) and collagen deposition. Our data demonstrate that bacterial sepsis contributes to the initiation of pulmonary fibrosis, and complement inhibition effectively attenuates the fibrotic response. This could be an attractive strategy for prevention of sepsis‐induced pulmonary fibrosis.