Losartan Intervention In A Rat Model Of Pulmonary Fibrosis Caused By Bleomycin And Its Possible Mechanism

Background Bloemycin(BLM) induced pulmonary fibrosis(BPF) is most widely used animal model for idiopathic pulmonary fibrosis. But the results of studies based on BPF are not always coincident with clinical condition. As all BPF models begin from an acute lung injury followed by wide spread inflammation, any agent which can alleviate the lung injury or inflammation may therefor alleviate the ultimate pulmonary fibrosis. More and more researches suggest the important role of angiotensin II in organ fibrosis. Earlier study of this laboratory also showed that losartan, a selective antagonist of angiotensin II type 1 receptor, alleviated BLM induced pulmonary fibrosis in rats. In the current study, we delayed the administration of losartan in order to discriminate the antifibrotic effect of this agent. Methods Male Sprague-Dawley rats, weighted 280±20 gram, were endotracheally instilled with BLM or normal saline (NS). Losartan or NS was given daily by gavage from the day before instillation of BLM. Rats were randomly separated into four groups: group N, endotracheal NS+ gavage NS; group B, endotracheal BLM+gavage NS; group L, endotracheal BLM+ gavage losartan; group L2, endotracheal BLM+gavage NS for the first week followed by gavage losartan thereafter. Animals were sacrificed and lungs were harvested 7, 21 and 42 days after BLM instillation. Lung collagen was stained by sinus red and measured by content of hydroxyproline. Expression of mRNAs of transforming growth factor-β₁ (TGF-β₁)and tumor necrosis factor-α(TNF-α) was detected by reverse transcription-polymerase chain reaction (RT-PCR). The direct impact of losartan on lung fibroblasts proliferation was assessed by MTT method. Results Pulmonary inflammation and collagen diposition were significantly attenuated with a significant decrease in lung content of hydroxyproline in group L compared with those in group B on the 21st and 49th days. There were no significant difference between group L2 and group B according to these indexes. Tissue expression of TGF-β₁ and TNF-α mRNAs was significantly enhanced 7 days after BLM instillation in group B. In animals with early application of losartan (group L), expression of TGF- mRNA was partially inhibited as compared with group B. Losartan has no direct influence on the proliferation of lung fibreblasts. Conclusions In this model of BPF, early...