| Objective: High-altitude pulmonary hypertension(HAPH)is a pulmonary vascular disease at high altitude areas,which is characterized by hypoxic pulmonary vasoconstriction and hypoxic pulmonary vascular remodeling.At present,there are few treatment options available for these patients,and the prognosis is poor.Halofuginone(HF)is a quinazolone extracted from the Chang Shan,which has anti-proliferative,antihypertrophic,anti-fibrotic and other effects,but it is unclear whether it has any therapeutic effect on HAPH.In this study,we explored the effect and possible mechanism of HF on HAPH by establishing a rat model of HAPH.Methods:1.Fifty male Sprague-Dawley(SD)rats were divided into the model group(MG),the sildenafil group(SI)and the HF low-dose,medium-dose and high-dose groups(HF-L,HF-M,HF-H),and the HAPH rat model was constructed in hypobaric hypoxia chamber;another 10 rats were fed outside the chamber as the control group(CG).Rats in the SI group were gavaged with SI 25 mg/kg,rats in the HF-L group were gavaged with HF 0.5 mg/kg,rats in the HF-M group were gavaged with HF 1 mg/kg,rats in the HF-H group were gavaged with HF 2 mg/kg,and rats in the CG and MG groups were gavaged with equal amounts of distilled water.The rats in each group were gavaged once a day for 4 weeks.The right ventricular systolic pressure(RVSP)was measured,the mean pulmonary artery pressure(m PAP)was calculated,and the morphological changes of small pulmonary artery were observed by hematoxylin-eosin(HE)staining to assess the degree of pulmonary vascular remodeling.The results were analyzed to evaluate the effect of HF on HAPH and to obtain the optimal dose of HF administration.2.Forty male SD rats were divided into the normoxia group(Nor),the normoxia + HF group(Nor + HF),the hypoxia group(Hyp),and the hypoxia + HF group(Hyp + HF).Rats in the Nor + HF and Hyp + HF groups were gavaged once daily with HF,and rats in the Nor and Hyp groups were gavaged once daily with equal amounts of distilled water.After 4 weeks,the RVSP was measured,the m PAP was calculated,the morphological changes of small pulmonary artery were observed by HE staining to assess the degree of pulmonary vascular remodeling,the levels of inflammatory factors IL-1β,IL-6 and TNF-α in lung tissue were detected by enzyme-linked immunosorbent assay,the expression of α-SMA in small pulmonary artery was detected by immunohistochemical staining,and the expressions of proliferative proteins PCNA,CDK6 and TGF-β1/Smad signaling pathway related proteins in lung tissue were detected by western blot.Results:1.(1)The effect of HF on HAPH: compared with the CG group,the RVSP and m PAP were significantly increased in the MG group(P < 0.001),and the small pulmonary artery wall was significantly thickened and the lumen was significantly narrowed;compared with the MG group,the RVSP and m PAP were decreased in SI and HF dose groups(P < 0.001),and the remodeling of small pulmonary artery showed different degrees of reduction;compared with the SI group,the reduction in RVSP and m PAP was weaker in the HF-L group(P < 0.001),and the improvement of small pulmonary artery remodeling in the HF-L group was inferior to that in the SI group;compared with the SI group,there was no significant difference in the reduction of RVSP and m PAP in the HF-M and HF-H groups(P > 0.05),and the improvement of small pulmonary artery remodeling was similar;the differences between HF-M and HF-H groups in reducing RVSP and m PAP were not statistically significant(P > 0.05),and the improvement of small pulmonary artery remodeling was similar.(2)The optimal dose of HF administration: 1 mg/kg.2.(1)Compared with the Nor group,the RVSP and m PAP were significantly increased in the Hyp group(P< 0.001),pulmonary vascular remodeling was significantly elevated,and inflammatory factors IL-1β,IL-6,TNF-α levels,proliferative proteins PCNA,CDK6 expressions and the expressions of TGF-β1/Smad signaling pathway related proteins in lung tissue were significantly increased(P < 0.05 or P < 0.01 or P <0.001);compared with the Hyp group,the RVSP and m PAP were significantly decreased in the Hyp + HF group(P < 0.001),the degree of pulmonary vascular remodeling was significantly alleviated,and inflammatory factors IL-1β,IL-6,TNF-α levels,proliferative proteins PCNA,CDK6 expressions and the expressions of TGF-β1/Smad signaling pathway related proteins in lung tissue were significantly decreased(P < 0.05).(2)By setting the Nor + HF group,it was found that there were no significant differences between the Nor and Nor + HF groups in RVSP,m PAP,inflammatory factors IL-1β,IL-6,TNF-α levels,proliferative proteins PCNA,CDK6 expressions and the expressions of TGF-β1/Smad signaling pathway related proteins in lung tissue(P > 0.05),and there was no pulmonary vascular remodeling in both groups of rats.These results suggested that HF had no significant effect on rats under normoxic environment.Conclusion:1.HF alleviates HAPH by reducing hemodynamic parameters and improving pulmonary vascular remodeling.2.The mechanism by which HF exerts its protective effect may be related to the inhibition of inflammatory and proliferative responses mediated by the TGF-β1/Smad signaling pathway. |
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