Reduction of bleomycin induced lung fibrosis by candesartan cilexetil, an angiotensin II type 1 receptor antagonist.
BACKGROUND
Signalling of angiotensin II via angiotensin II type 1 receptor (AT1) promotes cardiac and renal fibrosis, but its role in lung fibrosis is little understood. Using a rat bleomycin (BLM) induced model of pulmonary fibrosis, we examined the expression of AT1 in the lung and the effect of an AT1 antagonist on pulmonary fibrosis.


METHODS
Adult male Sprague-Dawley rats were given 0.3 mg/kg BLM intratracheally. Two days earlier they had received 10 mg/kg/day of the AT1 antagonist candesartan cilexetil mixed in the drinking water. AT1 expression in the lungs was examined by immunohistochemistry and immunoblot methods. The effect of the AT1 antagonist on pulmonary fibrosis was studied by analysis of bronchoalveolar lavage (BAL) fluid, histopathology, and hydroxyproline assay.


RESULTS
Immunohistochemical studies showed overexpression of AT1 in inflammatory immune cells, alveolar type II cells, and fibroblasts. A quantitative assay for AT1 showed that AT1 expression was significantly upregulated in cells from BAL fluid after day 3 and in the lung homogenates after day 21. Candesartan cilexetil significantly inhibited the increase in total protein and albumin, as well as the increase in total cells and neutrophils in BAL fluid. On day 21 candesartan cilexetil also ameliorated morphological changes and an increased amount of hydroxyproline in lung homogenates. In addition, BLM increased the expression of transforming growth factor (TGF)-beta1 in BAL fluid on day 7; this increase was significantly reduced by candesartan cilexetil.


CONCLUSIONS
AT1 expression is upregulated in fibrotic lungs. Angiotensin II promotes lung fibrosis via AT1 and, presumably, in part via TGF-beta1.
Otsuka
M
M
Third Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan.
Takahashi
H
H
Shiratori
M
M
Chiba
H
H
Abe
S
S
D000418:Albumins / Q000032:analysis; D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D000903:Antibiotics, Antineoplastic; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D001761:Bleomycin; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D006909:Hydroxyproline / Q000032:analysis; D007150:Immunohistochemistry; D008297:Male; D011506:Proteins / Q000032:analysis; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D013777:Tetrazoles; D016212:Transforming Growth Factor beta / Q000032:analysis; D053773:Transforming Growth Factor beta1
D000418:Albumins; D047228:Angiotensin II Type 1 Receptor Blockers; D000903:Antibiotics, Antineoplastic; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D011506:Proteins; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; C077793:candesartan cilexetil; D006909:Hydroxyproline