AIRWAY BIOLOGY

Attenuation of bleomycin induced pulmonary fibrosis in mice using the heme oxygenase inhibitor Zn-deuteroporphyrin IX-2,4-bisethylene glycol

L Atzori², F Chua¹, S E Dunsmore³, D Willis⁴, M Barbarisi¹, R J McAnulty¹, G J Laurent¹

¹ Centre for Respiratory Research, Royal Free and University College London Medical School, London, UK
² Department of Toxicology, University of Cagliari, Cagliari, Italy
³ Department of Pulmonary Medicine and Critical Care Medicine, Brigham and Women’s Hospital, Boston, USA
⁴ Department of Pharmacology, University College London, London, UK

Correspondence to:
Correspondence to:
Dr L Atzori
Centre for Respiratory Research, Royal Free and University College Medical School, 5 University Street, London WC1E 6JJ, UK; latzori{at}unica.it

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 µmol/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 ß (TGF-ß), 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.

Keywords: bleomycin; lung fibrosis; Zn-deuteroporphyrin-IX-2,4-bisethylene glycol; heme oxygenase

Abbreviations: HO, heme oxygenase; LDH, lactate dehydrogenase; MAL, malondialdehyde; TGF-ß, transforming growth factor ß; Zndtp, Zn-deuteroporphyrin IX-2,4-bisethylene glycol

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

Relevant Article

Airwaves

Wisia Wedzicha
Thorax 2004 59: 181. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

• Ye, Q., Dalavanga, Y., Poulakis, N., Sixt, S. U., Guzman, J., Costabel, U. (2008). Decreased expression of haem oxygenase-1 by alveolar macrophages in idiopathic pulmonary fibrosis. Eur Respir J 31: 1030-1036 [Abstract] [Full Text]  
• Fredenburgh, L. E., Perrella, M. A., Mitsialis, S. A. (2007). The Role of Heme Oxygenase-1 in Pulmonary Disease. Am. J. Respir. Cell Mol. Bio. 36: 158-165 [Abstract] [Full Text]  
• Ryter, S. W., Alam, J., Choi, A. M. K. (2006). Heme Oxygenase-1/Carbon Monoxide: From Basic Science to Therapeutic Applications. Physiol. Rev. 86: 583-650 [Abstract] [Full Text]  
• Morse, D., Choi, A. M. K. (2005). Heme Oxygenase-1: From Bench to Bedside. Am. J. Respir. Crit. Care Med. 172: 660-670 [Abstract] [Full Text]  

eLetters:

Read all eLetters

Dilemma of manipulating heme oxygenase (HO) activity to cure inflammatory diseases of the lung

Takahiro Tsuburai, et al.

Thorax Online, 4 May 2004 [Full text]