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In the April 2004 issue, Atzori and coworkers reported therapeutic effects of depleting HO activity on bleomycin-induced pulmonary fibrosis in mice.
Administration of an HO inhibitor (Zn-deuteroporphyrin IX-2,4-bisethylene glycol, Zndt) 7 days following bleomycin treatment was associated with pathological improvement, reduced accumulation of collagen, and TGF-beta1 level in the lung in a dose depe...
Administration of an HO inhibitor (Zn-deuteroporphyrin IX-2,4-bisethylene glycol, Zndt) 7 days following bleomycin treatment was associated with pathological improvement, reduced accumulation of collagen, and TGF-beta1 level in the lung in a dose dependent manner. The paper clearly demonstrates that at the latter phase of the pathological processes elicited by bleomycin, the presence of HO activity supports alveolar cell apoptosis and the development of pulmonary fibrosis by the oxidative activity of ferrous iron, a byproduct of HO-1 enzymatic activity. These observations, however, are in contrast to previous data suggesting that overexpression of HO in the lung provides therapeutic benefits in animals treated with hyperoxia, lipopolysaccharide, influenza virus, Pseudomonas aeruginosa, and bleomycin.[2-4]
It is important that most of these studies have used a gene transfer technique that provides transient excessive HO gene expression in a limited number of macrophages and alveolar cells. Since carbon monoxide (CO) and bilirubin both protect bleomycin-treated lung from massive pulmonary fibrosis, the therapeutic effect of using HO-1 cDNA could be attributed to the subsequent production of these molecules in the lung. The transient gene transfer strategy allows the production of sufficient CO and bilirubin from the transfected cells in the local milieu while minimizing harmful side effects of accumulating ferrous iron in the lung. It is critical to eliminate the deleterious effect of iron in order to maximize the potential benefit of using HO-1 as a novel therapeutic target in clinical situations. The dilemma of manipulating HO for inflammatory lung diseases could be resolved when the HO enzyme activity in the lung can be tightly controlled at an appropriate level at each stage of the disease.
1. Atzori, L., F. Chua, S. E. Dunsmore, et al. 2004. Attenuation of bleomycin induced pulmonary fibrosis in mice using the heme oxygenase inhibitor Zn-deuteroporphyrin IX-2,4-bisethylene glycol. Thorax 59(3):217-23.
2. Morse, D., and A. M. Choi. 2002. Heme oxygenase-1: the "emerging molecule" has arrived. Am J Respir Cell Mol Biol 27(1):8-16.
3. Tsuburai, T., T. Kaneko, Y. Nagashima, A. et al. 2004. Pseudomonas aeruginosa-induced neutrophilic lung inflammation is attenuated by adenovirus-mediated transfer of the heme oxygenase 1 cDNA in mice. Hum Gene Ther 15(3):273-85.
4. Tsuburai, T., M. Suzuki, Y. Nagashima, S. et al. 2002. Adenovirus-mediated transfer and overexpression of heme oxygenase 1 cDNA in lung prevents bleomycin-induced pulmonary fibrosis via a Fas-Fas ligand-independent pathway. Hum Gene Ther 13(16):1945-60.