Bleomycin-induced pulmonary fibrosis is attenuated in gamma-glutamyl transpeptidase-deficient mice.
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 microg 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.
Pardo
Annie
A
Instituto Nacional de Enfermedades Respiratorias, Tlalpan 4502, Col. Sección XVI, México DF, CP 14080, México.
Ruiz
Victor
V
Arreola
José Luis
JL
Ramírez
Remedios
R
Cisneros-Lira
José
J
Gaxiola
Miguel
M
Barrios
Roberto
R
Kala
Subbarao V
SV
Lieberman
Michael W
MW
Selman
Moisés
M
D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001761:Bleomycin / Q000009:adverse effects*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D003094:Collagen / Q000032:analysis; D003545:Cysteine / Q000032:analysis; D004195:Disease Models, Animal; D005978:Glutathione / Q000032:analysis; D007249:Inflammation; D007958:Leukocyte Count; D020780:Matrix Metalloproteinase 9 / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D009504:Neutrophils / Q000276:immunology; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D012720:Severity of Illness Index; D013997:Time Factors; D005723:gamma-Glutamyltransferase / Q000172:deficiency*
D001761:Bleomycin; D003094:Collagen; D005723:gamma-Glutamyltransferase; D020780:Matrix Metalloproteinase 9; D005978:Glutathione; D003545:Cysteine; D000111:Acetylcysteine