Cyclosporin A upmodulates bleomycin-induced pulmonary fibrosis in BALB/c mice.
BACKGROUND
Intratracheal instillation of bleomycin (Bleo) into rodents serves as a model for human lung fibrosis. Various mouse strains respond differently to Bleo, and BALB/c mice are relatively resistant.


OBJECTIVE
Since T lymphocytes have been shown to play a major role in this model, the effect of the immunomodulator cyclosporin A (CyA) on lung fibrosis was studied in Bleo-'resistant' BALB/c mice.


METHODS
Pulmonary fibrosis was induced by a single intratracheal (IT) instillation of Bleo. One of the four following treatments was given to one of four groups of female BALB/c mice: (1) Bleo-CyA: IT Bleo and daily intraperitoneal (IP) injections of CyA 100 mg/day starting 1 day before IT instillation of Bleo; (2) Bleo-Sal: IT Bleo and IP injections of saline; (3) Sal-CyA: IT saline and IP CyA 100 mg/kg; (4) Sal-Sal: IT and IP saline. The animals were killed on day 14. Fibrosis was evaluated by analysis of hydroxyproline and by quantitative image analysis of the fibrosis fraction. Ex vivo IFN-gamma, IL-4, IL-13 and IL-5 secretion by peribronchial lymphatic tissue lymphocytes was measured.


RESULTS
Pretreatment with CyA upmodulated Bleo-induced lung fibrosis in the Bleo-'resistant' BALB/c mice; hydroxyproline was higher in Bleo-CyA compared to Bleo-Sal animals and both hydroxyproline and fibrosis fraction measurements were higher in Bleo-CyA compared to Sal-Sal. Cytokine secretion by lymphocytes demonstrated increased IFN-gamma/IL-4 and IFN-gamma/IL-13 mean secretion ratios in the Bleo-CyA animals compared to the Bleo-Sal animals.


CONCLUSIONS
These results indicate that CyA upmodulates Bleo-induced lung fibrosis in Bleo-'resistant' BALB/c mice by allowing the emergence of a Th1 inflammatory response.
Lossos
Izadore S
IS
Lung Cellular and Molecular Biology Laboratory, Institute of Pulmonology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Or
Reuven
R
Ginzburg
Vallery
V
Christensen
Thomas G
TG
Mashriki
Yaffa
Y
Breuer
Raphael
R
D000818:Animals; D001761:Bleomycin / Q000009:adverse effects; D016572:Cyclosporine / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D011658:Pulmonary Fibrosis / Q000276:immunology / Q000503:physiopathology*
D007166:Immunosuppressive Agents; D001761:Bleomycin; D016572:Cyclosporine