Blocking angiotensin type 1 receptor modulates Thl-mediated and Th17-mediated responses in lipopolysaccharide-induced acute lung injury mice

Introduction

Losartan, an antagonist of angiotensin II (Ang II) type 1 receptor, is a potential therapeutic drug for acute lung injury (ALI). Recent reports suggest that losartan inhibits T-helper (Th)-1 immune response and ultimately attenuates inflammation in several angiotensin II-mediated inflammatory diseases [1],[2]. However, the possible protective mechanisms of losartan in ALI remain poorly understood. This study was to assess the effect of losartan on the lung Th polarization response in ALI.

Methods

C57BL/6 mice were randomly divided into three groups: control group, ALI group and ALI + losartan group. ALI animals received 2 mg/kg LPS; ALI + losartan animals received 2 mg/kg LPS and 15 mg/kg losartan 30 minute before intratracheal injection of LPS. The pathological changes were examined under an optical microscope. The mRNA expression levels of T-bet, GATA-3 and RORγt were determined by quantitative real-time reverse transcriptase-polymerase chain reaction.

Results

The increase in LW/BW induced by LPS was partly prevented by pretreated with losartan. Histologically, losartan effectively attenuated the LPS-induced lung hemorrhage, and leukocyte cell infiltration in the interstitium and alveolus. Meanwhile, the levels of IL-6 in lung tissue were significantly enhanced in the LPS-induced ALI mice. With pretreatment of ALI mice with losartan, the level of IL-6 in lungs markedly decreased. The mRNA expression of T-bet and RORγt was upregulated in ALI mice at 24 hours and 48 hours relative to normal mice (P < 0.05 vs. Con). There was no significant difference in the expression of GATA-3 among groups at 24 hours and 48 hours. Of note, pretreatment of ALI mice with losartan resulted in significantly reduced mRNA expression of T-bet at 24 hours and 48 hours and RORγt mRNA expression at 48 hours (P < 0.05 vs. ALI). Meanwhile, the levels of IFNγ, IL-4, IL-17 and IL-6 in lung tissue were significantly enhanced at 24 hours and 48 hours in the LPS-induced ALI mice. In addition, both IFNγ and IL-17 in lung tissue at 24 hours and 48 hours decreased significantly in losartan-pretreated mice compared with the ALI mice. With pretreatment of ALI mice with losartan, the level of IL-4 in lungs was not changed.

Conclusion

Ang II-induced Th1 and Th17 polarization response could upregulate inflammatory response and induce lung injury, and losartan may be a promising substance for clinical use in LPS-induced ALI.