Attenuation of bleomycin induced pulmonary fibrosis in mice using the heme oxygenase inhibitor Zn-deuteroporphyrin IX-2,4-bisethylene glycol.
BACKGROUND
Pulmonary fibrosis is associated with a poor prognosis. The pathogenesis of fibrotic lung disorders remains unclear, but the extent of tissue damage due to the persistent presence of oxidants or proteases is believed to be important. The heme degrading enzyme heme oxygenase (HO) has been found to be expressed in experimental fibrosis, and generation of free iron and carbon monoxide (CO) by HO has been implicated in oxidant induced lung damage. A study was undertaken to examine the effects of the HO inhibitor Zn-deuteroporphyrin-IX-2,4-bisethylene glycol (Zndtp) on the development of pulmonary fibrosis in the bleomycin model of lung injury and repair.


METHODS
Zndtp (10 micro mol/kg) was administered subcutaneously twice daily to mice 1 week following the intratracheal instillation of 0.025 U bleomycin. Animals were killed 10 or 21 days after bleomycin instillation and indices of lung damage and fibrosis were evaluated.


RESULTS
Bleomycin treatment induced pulmonary cytotoxicity, increased levels of active transforming growth factor beta (TGF-beta), enhanced lung collagen accumulation, and decreased glutathione content. Zndtp administration significantly attenuated these indices.


CONCLUSIONS
Administration of Zndtp in the bleomycin model resulted in appreciable alveolar cytoprotection and amelioration of pulmonary fibrosis. This molecule and its analogues may warrant further consideration in the treatment of acute lung injury and fibrotic lung disorders.
Centre for Respiratory Research, Royal Free and University College London Medical School, London, UK. latzori@unica.it
L
L
Atzori
F
F
Chua
S E
SE
Dunsmore
D
D
Willis
M
M
Barbarisi
R J
RJ
McAnulty
G J
GJ
Laurent
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D001663:Bilirubin / Q000097:blood; D001761:Bleomycin / Q000633:toxicity*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D003905:Deuteroporphyrins / Q000627:therapeutic use*; D005978:Glutathione / Q000032:analysis; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors*; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D007962:Leukocytes / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000517:prevention & control; D016212:Transforming Growth Factor beta / Q000032:analysis
D000964:Antimetabolites, Antineoplastic; D003905:Deuteroporphyrins; D016212:Transforming Growth Factor beta; D001761:Bleomycin; C060750:zinc deuteroporphyrin IX 2,4-bis(glycol); D008315:Malondialdehyde; D007770:L-Lactate Dehydrogenase; D006419:Heme Oxygenase (Decyclizing); D005978:Glutathione; D001663:Bilirubin