Protection from pulmonary fibrosis in leukotriene-deficient mice.
Although overproduction of proinflammatory 5-lipoxygenase (5-LO)-derived leukotrienes (LTs) has been demonstrated in the lungs of patients with pulmonary fibrosis, their causal involvement in this condition has not been established. Bleomycin-induced pulmonary fibrosis was studied in mice rendered LT deficient by knockout of the 5-LO gene (KO) and in wild-type (WT) control mice. Following administration of bleomycin, lung lavage fluid of WT mice demonstrated an approximately 5-fold increase in levels of cysteinyl-LTs over baseline levels at Day 1, with persistent elevation up to Day 21. As compared with WT mice, 5-LO KO mice demonstrated reduced amounts of histologically evident collagen as well as an approximately 60% reduction in lung hydroxyproline levels postbleomycin. Unlike WT mice, KO mice showed no increases in the numbers of lung inflammatory cells postbleomycin. Furthermore, in situ expression and stimulated production by mixed lung leukocytes of the antifibrotic cytokine interferon-gamma were significantly greater in cells from the 5-LO KO mice. Finally, lavage levels of the antiinflammatory and antifibrotic molecule, prostaglandin E(2), were significantly greater in the KO animals. These results provide strong evidence that LTs may participate in the pathogenesis of pulmonary fibrosis, and they may do so by direct effects as well as indirect effects occurring via their modulation of the synthesis of other inflammatory mediators.
Peters-Golden
Marc
M
Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan 48109-0642, USA. petersm@umich.edu
Bailie
Marc
M
Marshall
Teresa
T
Wilke
Carol
C
Phan
Sem H
SH
Toews
Galen B
GB
Moore
Bethany B
BB
D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects; D001094:Arachidonate 5-Lipoxygenase / Q000172:deficiency / Q000502:physiology; D001761:Bleomycin / Q000009:adverse effects; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D003545:Cysteine / Q000032:analysis; D015232:Dinoprostone / Q000032:analysis; D004195:Disease Models, Animal; D015777:Eicosanoids / Q000032:analysis; D006909:Hydroxyproline / Q000032:analysis; D015289:Leukotrienes / Q000032:analysis / Q000172:deficiency* / Q000502:physiology*; D008168:Lung / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control*
D000900:Anti-Bacterial Agents; D015777:Eicosanoids; D015289:Leukotrienes; C112381:cysteinyl-leukotriene; D001761:Bleomycin; D001094:Arachidonate 5-Lipoxygenase; D015232:Dinoprostone; D003545:Cysteine; D006909:Hydroxyproline