The Protective Effects And Mechanism Of STV-na On Airway Hyper-responsiveness In Rat Model Of Mct Induced Pulmonary Arterial Hypertension

Pulmonary arterial hypertension(PAH)is a serious cardiopulmonary disease characterized by pulmonary arterial remodeling and progressive elevation of pulmonary arterial pressure.Although PAH has been widely studied in recent years,its pathegenesis remains unclear.At present,all drugs used to treat PAH can only relieve disease symptoms to protect PAH patients.Airway hyper-responsiveness is the abnormal reaction of airway to irritations,inflammation is one of the major causes of airway hyper-responsiveness.Previous studies have shown a close relationship between pulmonary arterial hypertension and airway hyper-responsiveness.An exact understanding of such may provide insights of the pathogenic mechanism of PAH and facilitate the discovery of new drugs for the disease.Isosteviol sodium(STV-Na)is a tetracyclic diterpenoid compound derived from stevioside.In the past,a large number of animal experiments showed that STV-Na has some protective effects on cardiovasular system,including protection from cardiopulmonary diseases and anti-inflammation effects.The aim of this study was to investigate the effects of STV-Na on airway hyper-responsiveness in rats with pulmonary arterial hypertension induced by monocrotaline(MCT)and the effects of STV-Na on the inflammatory cytokines in circulation or lung of PAH rats.The study may help understand the pathogenesis of PAH and explore the possible mechanism of using STV-Na to treat the disease.The main research contents are were as follows:(1)We investigated the effect of STV-Na on the reported symptoms of rats with pulmonary arterial hypertension induced by monocrotaline.The results showed that compared with the control group,the body weight,blood oxygen saturation,right ventricular hypertrophy index and BMPR-II and CD31 mRNA expression in the lung tissue were all affected by PAH-related symptoms,part of this change can be reversed from STV-Na to some extent.(2)We evaluated the effect of STV-Na on airway reactivity and degree of reversibility of PAH rat by bronchial provocation test and bronchil dialation test respectively.The results showed that,when compared with the control group,the PAH model group is more sensitive to the stimulation by MCh-cl(increased responsiveness),with increased airway resistance anddecreased lung compliance.Compared with the PAH model group,the responsiveness of STV-Na treatment group was slightly lower.PAH induced airway hyper-responsiveness could be reversed by the ?2 receptor blocker.STV-Na treatment could increase the degree to which airway hyper-responsiveness could be reversed.(3)We studied the influence of STV-Na on inflammatory factors in PAH rats using blood smear classification count,enzyme-linked immunosorbent assay and quantitative PCR method.The percentage of lymphocyte increased and the percentage of monocyte and polykaryocyte decreased in the plasma of PAH rats.STV-Na could partialy alleviate such pathological changes.The expression of TNF-? and TGF-?1 mRNA was significantly increased in lung tissue of PAH model rat and STV-Na could significantly reduce expression of m RNA of these inflammatory factors,especially the expression of TGF-?1.The results from the ELISA analysis of inflammatory factors in blood were similar.In addition,levels of C-reactive protein(CRP),a circulating marker commonly used for inflammation,were studied.The results showed that the level of CRP in the model group was higher than that in the STV-Na treatment group,but the trend was not obvious.These results suggested increased airway responsiveness in rat with PAH induced by MCT,which could be related to inflammation.STV-Na treatment is likely to alleviate airway hyper-responsiveness by reducing inflammation through inhibiting the expression of cytokines such as TGF-?1 and TNF-?.These findings have a certain exploratory significance for the development of new drugs for pulmonary arterial hypertension.