Bleomycin-induced pulmonary fibrosis is attenuated in γ-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, Moisés Selman

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

To investigate repair mechanisms in bleomycin-induced pulmonary fibrosis, we used mice deficient in γ-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.

Original languageEnglish (US)
Pages (from-to)925-932
Number of pages8
JournalAmerican journal of respiratory and critical care medicine
Volume167
Issue number6
DOIs
StatePublished - Mar 15 2003

Keywords

  • Cysteine
  • Glutathione
  • Matrix metalloproteinase-9
  • Neutrophils

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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