Delayed inflammatory responses to endotoxin in fibrinogen-deficient mice.
Severe inflammation leads to haemostatic abnormalities, such as the development of microvascular thrombi. As a result, ischaemia-related downstream organ damage can occur. The present study demonstrates that mice with a total deficiency of fibrinogen (Fg(-/-)) present with altered responses to challenge with Gram-negative lipopolysaccharide (LPS). Early survival in response to continuous LPS challenge was increased in Fg(-/-) mice and histological findings indicated that this improvement correlated with a lack of fibrin deposition in organs. Neutrophils appeared early in the lungs of challenged wild-type (WT) mice, but occurred in Fg(-/-) mice at later times. This delayed response in Fg(-/-) mice was confirmed by studies that showed a strong dependence on Fg of binding of neutrophils to endothelial cells in the presence of LPS. While cytokines were also elevated in both WT and Fg(-/-) mice, their levels were generally lower at early times in this latter group. The time course of MIP-2 expression correlated with the occurrence of pulmonary leakage after LPS challenge, which was delayed in Fg(-/-) mice. These results suggest that fibrin(ogen) plays a role as an early mediator in the cross-talk between coagulation and inflammation.
Cruz-Topete
D
D
WM Keck Center for Transgene Research and the Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
Iwaki
T
T
Ploplis
V A
VA
Castellino
F J
FJ
D000347:Afibrinogenemia / Q000276:immunology*; D000418:Albumins / Q000032:analysis; D000818:Animals; D000990:Antithrombin III; D015415:Biomarkers / Q000032:analysis; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002460:Cell Line; D016207:Cytokines / Q000097:blood; D019040:E-Selectin / Q000097:blood; D042783:Endothelial Cells / Q000276:immunology; D005337:Fibrin / Q000032:analysis; D005340:Fibrinogen / Q000032:analysis; D007249:Inflammation / Q000276:immunology*; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000276:immunology*; D008168:Lung / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D009569:Nitric Oxide / Q000097:blood; D010447:Peptide Hydrolases / Q000097:blood; D009195:Peroxidase / Q000032:analysis; D013997:Time Factors
D000418:Albumins; D015415:Biomarkers; D016207:Cytokines; D019040:E-Selectin; D008070:Lipopolysaccharides; C046193:antithrombin III-protease complex; D009569:Nitric Oxide; D000990:Antithrombin III; D005337:Fibrin; D005340:Fibrinogen; D009195:Peroxidase; D010447:Peptide Hydrolases