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Published ahead of print on December 4, 2002, doi:10.1164/rccm.200209-1007OC
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American Journal of Respiratory and Critical Care Medicine Vol 167. pp. 925-932, (2003)
© 2003 American Thoracic Society

Original Article

Bleomycin-induced Pulmonary Fibrosis Is Attenuated in {gamma}-Glutamyl Transpeptidase–Deficient Mice

Annie Pardo, Víctor Ruiz, José Luis Arreola, Remedios Ramírez, José Cisneros-Lira, Miguel Gaxiola, Roberto Barrios, Subbarao V. Kala, Michael W. Lieberman and Moisés Selman

Facultad de Ciencias, Universidad Nacional Autónoma de México, Circuito Exterior S/N, México; Department of Pathology, Baylor College of Medicine, Houston, Texas; and Instituto Nacional de Enfermedades Respiratorias, Tlalpan, México DF, México

Correspondence and requests for reprints should be addressed to Moisés Selman, M.D., Instituto Nacional de Enfermedades Respiratorias, Tlalpan 4502, Col. Sección XVI, México DF, CP 14080, México. E-mail: mselman{at}sni.conacyt.mx

To investigate repair mechanisms in bleomycin-induced pulmonary fibrosis, we used mice deficient in {gamma}-glutamyl transpeptidase (GGT-/-), a key enzyme in glutathione (GSH) and cysteine metabolism. Seventy-two hours after bleomycin (0.03 U/g), GGT-/- mice displayed a different inflammatory response to wild-type mice as judged by a near absence of neutrophils in lung tissue and bronchoalveolar lavage and a less pronounced rise in matrix metalloproteinase-9. Inflammation in GGT-/- mice consisted mainly of lymphocytes and macrophages. At 1 month, lungs from bleomycin-treated GGT-/- mice exhibited minimal areas of fibrosis compared with wild-type mice(light microscopy fibrosis index: 510 ± 756 versus 1975 ± 817, p < 0.01). Lung collagen content revealed a significant increase in bleomycin-treated wild-type (15.1 ± 3.8 versus 8.5 ± 0.7 µg hydroxy(OH)-proline/mg dry weight, p < 0.01) but not in GGT-/- (10.4 ± 1.7 versus 8.8 ± 0.8). Control lungs from GGT-/- showed a significant reduction of cysteine (0.03 ± 0.005 versus 0.055 ± 0.001, p < 0.02) and GSH levels (1.24 ± 0.055 versus 1.79 ± 0.065, p < 0.002). These values decreased after 72 hours of bleomycin in both GGT-/- and wild-type but reached their respective control values after 1 month. Supplementation with N-acetyl cysteine partially ameliorated the effects of GGT deficiency. These findings suggest that increased neutrophils and matrix metalloproteinase-9 during the early inflammatory response and adequate thiol reserves are key elements in the fibrotic response after bleomycin-induced pulmonary injury.

Key Words: glutathione • matrix metalloproteinase-9 • neutrophils • cysteine




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