The Role Of HIF-1α And VEGF In Airway Remodeling Of Asthmatic Rat Exposed To Smoke And The Therapeutic Effect Of Sirolimus

Objective Research shows that,compared with non-smoking athma patients,smoking asthma patients are easy to experience severer symptoms, more exacerbations,poorer glucocorticoid (here in after referred to as hormone) curative effect, and evensudden death.Currently, airway remodeling pathogenesis of athma patients withsmoking is not clear, Our preliminary research results show that the asthmatic rat waswith obvious airway neutrophils infiltrating and sirolimus could significantly inhibitneutrophilic inflammation in athma rats exposed to smoke. Studies have shown thatPI3K/AKT signaling pathway plays a key role in the growth and proliferation ofairway smooth muscle by adjusting HIF-1alpha and VEGF. It may be selectivetargets for the prevention and control of the airway remodeling of asthma. mTOR isone of the important downstream of PI3K/AKT signal pathway. This studyhypothesizes HIF-1alpha and VEGF may be associated with airway remodeling ofthe asthma exposed to smoke and sirolimus, mTOR inhibitor, may have therapeuticeffect for asthma exposed to smoke.This study is to explore the expression of HIF-1alpha and of VEGF after the establishment of OVA sensitized asthma rats model ofsmoke exposure, thus to learn the influence of HIF-1alpha and of VEGF on airwayremodeling and the effect of sirolimus on the model.Methods1. Rat model of asthma exposed to smoke is established.The rats wererandomly divided into four groups: normal control group, smoke group, asthma（OVA sensitization） group, asthma exposed to smoke（smoke exposure and OVAsensitization）group. Each group of rats were sacrificed and have lung tissue stainedafter the establishment of the model.Airway smooth muscle(ASM) thickness weremeasured by image analysis software Iviewer, The mRNA of HIF-1alpha andVEGF from lung tissue were detected by RT-PCR, protein of HIF-1alpha and VEGFfrom lung tissue were detected by Western-blot or ELISA respectively.2. Discuss theexpression of HIF-1α,VEGF and the thickness of ASM,then learn the correlationanalysis of them.3. Therapeutic effect of sirolimus in the treatment of airway remodeling in asthma model and asthma exposed to smoke model and the mechanism.The rats were randomly divided into five groups: normal control group,asthma group;asthma treated with sirolimus group; asthma exposed to smoke group, asthma exposedto smoke treated with sirolimus group. The models were established as step1.Sirolimus were given with gavage in the.sirolimus treated group,other qroups weregiven orange juice with gavage instead. Data collection and analysis were as same asthe above.Results1.We successfully established asthma exposed to smoke model.Compared with normal control group and smoke exposure group, the thickness ofASM significantly increased in the asthma group and asthma exposed to smoke group(p＜0.05).Compared with normal control group, the mRNA and proteinlevel of VEGFin the lung tissue significantly increased in the smoke group and asthmatic models andasthmatic models exposed to smoke (p＜0.05).Compared with normal control group,the mRNA and protein level of HIF-1α in the lung significantly increased in the smokegroup and asthma group and asthma exposed to smoke group (p＜0.05).2.Thecorrelation analysis of HIF-1α and VEGF to the airway remodeling in asthma exposedto smoke.①the protein level of HIF-1α in the lung tissue is positively correlated withthe protein level of VEGF (r=0.459, P＜0.05);②the protein level of VEGF in thelung tissue is positively correlated with the thickness of ASM (r=0.814, P＜0.01).③the protein level of HIF-1α in the lung tissue is positively correlated with the thicknessof ASM (r=0.590, P＜0.01).3. The therapeutic effect of sirolimus in the treatment ofairway remodeling in asthma and asthma exposed to smoke and themechanism.Compared with athma group which was not treated with sirolimus, theprotein and mRNA level of VEGF in lung tissue and the thickness of ASM was seengreat remissionin the goup of athma group treated with sirolimus （p＜0.05).Compared with athma exposed to smoke group which was not treated with sirolimus,the mRNA level and protein level of HIF-1α in lung tissue and the thickness of ASMwas seen great remission in the goup of athma exposed to smoke group treated withsirolimus（p＜0.05).while the protein and mRNA level of VEGF in lung tissue werehigher in the athma exposed to smoke group treated with sirolimus than athma exposedto smoke group which was not treated with sirolimus,though without statisticalsignificance（p＞0.05). Conclusion1.The expression of HIF-1alpha and VEGF and the thickness of ASMincreased in athma group and athma exposed to smoke group.2.The expression of HIF-1alpha in athma rats exposed to smoke may up-regulate the expression of VEGFexpression level.It may be one of the pathogenesis of airway remodeling in asthmaexposed to smoke.3. Sirolimus may decrease VEGF expression level and reduce thethickness of airway smooth muscle therefore, the future sirolimus may have potentialtherapeutic effect in asthmatic airway remodeling.4. Sirolimus may decrease HIF-1alpha expression level and reduce the thickness of airway smooth muscle. Butsirolimus shows no inhibition to the expression of VEGF. Therefore, the futuresirolimus may have potential therapeutic effect in in asthmatic airwayremodeling.Effect of sirolimus on asthma exposed to smoke needs to be studiedfurther.