Reduction in fibrotic tissue formation in mice genetically deficient in plasminogen activator inhibitor-1.
Mice with homozygous deletion of the plasminogen activator inhibitor-1 gene (PAI-1(-/-)) are relatively protected from bleomycin-induced pulmonary fibrosis. At least part of the protective effect appears to occur during the latter stages of the pathological process when fibrotic tissue is being deposited. To investigate the effect of PAI-1 deficiency on fibrosis, we studied the accumulation of fibrotic tissue within subcutaneously implanted polyvinyl alcohol sponges. Similar to the effect of PAI-1 deficiency on bleomycin-induced pulmonary fibrosis, the accumulation of fibrotic tissue within implanted sponges occurred more slowly in PAI-1(-/-) compared to wild-type mice. Another striking difference observed in the PAI-1(-/-) mice was the rapid removal of a fibrin-rich matrix that formed within the sponges by 1 day after implantation in both wild-type and PAI-1(-/-) mice. The pattern of connective tissue invasion also differed: cells in wild-type mice infiltrated as individually penetrating cells whereas in PAI-1(-/-) mice they did so as a well-demarcated advancing front. Providing an alternative provisional matrix by impregnating sponges with a low concentration of collagen before implantation corrected the changes induced by PAI-1 deficiency. In conclusion, PAI-1 deficiency appears to affect fibrotic tissue formation in part by altering the provisional matrix that forms soon after tissue injury.
Chuang-Tsai
Sheila
S
Department of Internal Medicine, Pulmonary and Critical Care Medicine Division, University of Michigan Health Sciences Center, Ann Arbor, Michigan 48109, USA.
Sisson
Thomas H
TH
Hattori
Noboru
N
Tsai
Christopher G
CG
Subbotina
Natalya M
NM
Hanson
Kerstin E
KE
Simon
Richard H
RH
D000818:Animals; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology*; D005547:Foreign Bodies; D006909:Hydroxyproline / Q000378:metabolism; D008168:Lung / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics* / Q000378:metabolism; D011142:Polyvinyl Alcohol; D019736:Prostheses and Implants
D017395:Plasminogen Activator Inhibitor 1; D005337:Fibrin; D011142:Polyvinyl Alcohol; D003094:Collagen; D006909:Hydroxyproline