Inhibition of experimental acute pulmonary inflammation by pirfenidone.
Pirfenidone, a putative tumor necrosis factor-alpha (TNF-alpha) inhibitor, has recently gained recognition for its therapeutic use in the treatment of idiopathic pulmonary fibrosis. As pulmonary fibrosis may be the result of lung inflammatory processes, we examined the anti-inflammatory potential of pirfenidone in several models of acute pulmonary inflammation. In antigen-induced allergic paradigms, 24 h after antigen challenge, sensitized mice or guinea pigs develop a prominent pulmonary inflammation, reflected by a significant increase in the number of recoverable bronchoalveolar lavage (BAL) total cells and eosinophils. In both species, the pretreatment of animals with pirfenidone (10 and 30 mg/kg) resulted in a dose-dependent inhibition of the antigen-induced pulmonary inflammation, which was reflected by a significant decrease in the BAL eosinophils and total cells by the 30 mg/kg dose. In a non-allergic model of pulmonary inflammation, rats challenged with intratracheal LPS develop a significant increase in BAL neutrophils and total cells, along with significant increases in TNF-alpha and IL-6. Pretreatment with pirfenidone (3 and 30 mg/kg) showed a dose-dependent inhibition of the LPS-induced pulmonary inflammation, reflected by a significant decrease in the number of BAL total and neutrophilic cells at both the 3 and 30 mg/kg dose. However, pirfenidone had no effect on the peak BAL levels of TNF-alpha. In contrast, pirfenidone significantly inhibited BAL levels of IL-6. In summary, we have shown that pirfenidone can inhibit allergic and non-allergic inflammatory cell recruitment and that its pulmonary anti-inflammatory activity is independent of TNF-alpha inhibition.
Spond
J
J
Schering Plough Research Institute, Allergy and Immunology, 2015 Galloping Hill Road, K-15-1600, Kenilworth, NJ 07033, USA.
Case
N
N
Chapman
R W
RW
Crawley
Y
Y
Egan
R W
RW
Fine
J
J
Hey
J A
JA
Kreutner
W
W
Kung
T
T
Wang
P
P
Minnicozzi
M
M
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006168:Guinea Pigs; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D011014:Pneumonia / Q000209:etiology / Q000517:prevention & control*; D029424:Pulmonary Disease, Chronic Obstructive / Q000517:prevention & control; D011728:Pyridones / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015850:Interleukin-6; D008070:Lipopolysaccharides; D011728:Pyridones; D014409:Tumor Necrosis Factor-alpha; C093844:pirfenidone