Heparin attenuates bleomycin but not silica-induced pulmonary fibrosis in mice: possible relationship with involvement of myofibroblasts in bleomycin, and fibroblasts in silica-induced fibrosis.
Pulmonary fibrosis was elicited in mice or rats by the intratracheal instillation of bleomycin or silica. Daily injections of heparin significantly reduced the collagen deposition in bleomycin, but not in silica, injected mice, as evaluated by the lung hydroxyproline content on day 15 after instillation. Heparin also reduced the bleomycin-induced morbidity and mortality. Study of the broncho-alveolar lavage fluid (BAL) detected no significant change in the number of leucocytes or the amount of protein in heparin treated mice. Histologies of bleomycin instilled mice suggested that heparin did reduce the alveolar remodelling but not the alveolitis, evidenced by leucocytic infiltration. As detected by electron microscopy (EM), bleomycin increased the number of leucocytes and platelets within the alveolar capillaries but this was not significant ly reduced by heparin. The phenotype of the interstitial cell involved in these two types of pulmonary fibrosis was investigated by immunohistochemistry and EM. While in bleomycin injected animals the interstitial cells had the phenotype of an actin (alpha-actin in the rat) and lipid containing interstitial cell, with a poorly developed RE, in silica injected animals in contrast, the interstitial cells were without cytoplasmic actin or lipid but with a markedly developed endoplasmic reticulum (ER). Thus bleomycin and silica induced the growth of two different types of interstitial cells, the myofibroblast and the regular fibroblast, which might be a reason why heparin selectively inhibits bleomycin but not silica-induced fibrosis.
Piguet
P F
PF
Amgen Inc, Thousand Oaks, Ca. 91320-1789, USA.
Van
G Y
GY
Guo
J
J
D000818:Animals; D001761:Bleomycin / Q000633:toxicity*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000473:pathology; D006493:Heparin / Q000627:therapeutic use*; D006909:Hydroxyproline / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008854:Microscopy, Electron; D011658:Pulmonary Fibrosis / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D012822:Silicon Dioxide / Q000633:toxicity*
D003598:Cytoskeletal Proteins; D001761:Bleomycin; D012822:Silicon Dioxide; D006493:Heparin; D006909:Hydroxyproline