Cysteinyl leukotrienes are autocrine and paracrine regulators of fibrocyte function.
Pulmonary fibrosis is characterized by the accumulation of fibroblasts and myofibroblasts. These cells may accumulate from three potential sources: the expansion of resident lung fibroblasts, the process of epithelial-mesenchymal transition, or the recruitment and differentiation of circulating mesenchymal precursors known as fibrocytes. We have previously demonstrated that fibrocytes participate in lung fibrogenesis following administration of FITC to mice. We now demonstrate that leukotriene-deficient 5-LO(-/-) mice are protected from FITC-induced fibrosis. Both murine and human fibrocytes express both cysteinyl leukotriene receptor (CysLT) 1 and CysLT2. In addition, fibrocytes are capable of producing CysLTs and can be regulated via the autocrine or paracrine secretion of these lipid mediators. Exogenous administration of leukotriene (LT) D(4), but not LTC(4) induces proliferation of both murine and human fibrocytes in a dose-dependent manner. Consistent with this result, CysLT1 receptor antagonists are able to block the mitogenic effects of exogenous LTD(4) on fibrocytes. Endogenous production of CysLTs contributes to basal fibrocyte proliferation, but does not alter fibrocyte responses to basic fibroblast growth factor. Although CysLTs can induce the migration of fibrocytes in vitro, they do not appear to be essential for fibrocyte recruitment to the lung in vivo, possibly due to compensatory chemokine-mediated recruitment signals. However, CysLTs do appear to regulate the proliferation of fibrocytes once they are recruited to the lung. These data provide mechanistic insight into the therapeutic benefit of leukotriene synthesis inhibitors and CysLT1 receptor antagonists in animal models of fibrosis.
Vannella
Kevin M
KM
Immunology Graduate Program, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
McMillan
Tracy R
TR
Charbeneau
Ryan P
RP
Wilke
Carol A
CA
Thomas
Peedikayil E
PE
Toews
Galen B
GB
Peters-Golden
Marc
M
Moore
Bethany B
BB
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000172:deficiency; D019898:Autocrine Communication / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects / Q000276:immunology; D003545:Cysteine / Q000494:pharmacology / Q000502:physiology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016650:Fluorescein-5-isothiocyanate / Q000494:pharmacology; D006801:Humans; D015289:Leukotrienes / Q000494:pharmacology / Q000502:physiology*; D008565:Membrane Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019899:Paracrine Communication / Q000276:immunology*; D011658:Pulmonary Fibrosis / Q000276:immunology* / Q000517:prevention & control; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D018077:Receptors, Leukotriene / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013329:Structure-Activity Relationship
D015289:Leukotrienes; D008565:Membrane Proteins; D012333:RNA, Messenger; D018077:Receptors, Leukotriene; C112381:cysteinyl-leukotriene; C412375:cysteinyl leukotriene receptor 2; D001094:Arachidonate 5-Lipoxygenase; D016650:Fluorescein-5-isothiocyanate; D003545:Cysteine; C083169:leukotriene D4 receptor