Modulation of airway remodeling-associated mediators by the antifibrotic compound, pirfenidone, and the matrix metalloproteinase inhibitor, batimastat, during acute lung injury in mice.
Matrix metalloproteinases (MMPs) are potent to degrade basement membrane collagen associated with acute lung injury in inflammatory processes. We have investigated effects of pirfenidone, antifibrotic agent, and batimastat, inhibitor of MMPs, on gelatinase activities, on release of tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta), as well as on recruitment of inflammatory cells in bronchoalveolar lavage (BAL) fluid after aerosol administration of lipopolysaccharide (LPS) in mice. Pretreatment with pirfenidone reduced neutrophil recruitment, TNF-alpha and TGF-beta levels, and MMP-9 secretion. In contrast, pretreatment with batimastat (30 or 60 mg/kg, i.p.) only reduced TNF-alpha and TGF-beta levels. Batimastat did not reduce MMP secretion in BAL fluid but inhibited MMP-9 activity. The increase in tissue inhibitor of matrix metalloproteinase (TIMP)-1 induced by LPS was not modified by the two drugs. These findings demonstrate that the two drugs can inhibit the in vivo increase in MMP induced by LPS, batimastat with a direct inhibitor effect on MMP activity and pirfenidone as a consequence of its antiinflammatory effect.
Corbel
M
M
INSERM U 456, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes 1, 2 Avenue du Professeur Léon Bernard, 35043, Rennes, France.
Lanchou
J
J
Germain
N
N
Malledant
Y
Y
Boichot
E
E
Lagente
V
V
D000208:Acute Disease; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002452:Cell Count; D018836:Inflammation Mediators / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008171:Lung Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D019714:Tissue Inhibitor of Metalloproteinases / Q000187:drug effects / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D061965:Matrix Metalloproteinase Inhibitors; D011728:Pyridones; D013876:Thiophenes; D019714:Tissue Inhibitor of Metalloproteinases; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D010649:Phenylalanine; C080985:batimastat; C093844:pirfenidone; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2