Potential Value Of The CX3CL1/CX3CR1 Chemokine System And Adma In Pulmonary Hypertension

Background: Pulmonary hypertension(PH)is a group of malignant pulmonary vascular diseases characterized by pulmonary vascular remodeling and a progressive increase in pulmonary vascular resistance.During the process of pulmonary vascular remodeling,all three layers of the pulmonary artery wall have undergone major changes,including intimal endothelial cell dysfunction,hyperplasia of medial smooth muscle cells,proliferation of adventitial fibroblasts and recruitment of immune cells.Multiple studies have confirmed that binding CX3CL1 to its receptor CX3CR1 can promote the recruitment of inflammatory cells and participate in the pathological processes of various inflammatory diseases,such as vasculitis and atherosclerosis.While estrogen and its metabolites have significant anti-inflammatory effects,17β-estradiol can partially reverse the development of hypoxic pulmonary hypertension.Whether E2 regulates the CX3CL1/CX3CR1 chemokine system in the process of relieving pulmonary hypertension,that is,whether CX3CL1/CX3CR1 chemokine system can be a targeted treatment point for E2 to reduce pulmonary hypertension is not clear.In addition,the social awareness rate of pulmonary hypertension is low and the diagnosis is complicated,and the rate of missed diagnosis and misdiagnosis is high in clinical.Many patients are not diagnosed until the disease progresses to advanced stages,and have lost the best time for treatment.Therefore,seeking objective and accurate detection indicators for the diagnosis and evaluation of PH has become a research hotspot.Part one 17β-estradiol reduces macrophage recruitment by regulating the CX3CL1/CX3CR1 chemokine systemObjective: To investigate whether the CX3CL1/CX3CR1 chemokine system can become a targeted treatment point for 17β-estradiol to reduce pulmonary hypertension,that is,whether E2 can reduce the recruitment of macrophages and ultimately reduce PH by regulating the CX3CL1/CX3CR1 chemokine system.Methods:Alveolar macrophages were cultured and randomly divided into normoxic group,hypoxic group,and hypoxia+E2 group.Macrophage recruitment was observed with an inverted microscope;CX3CL1 and CX3CR1 m RNA transcription levels in each group of cells were detected by RT-PCR;and CX3CL1 and CX3CR1 protein translation levels in each group of cells were detected by Western blot.Results:1.Inverted microscope results showed that macrophage recruitment was significantly lower in the hypoxic group than in the normoxic group,while E2 could attenuate the recruitment of macrophages in hypoxia.2.RT-PCR method detected that the transcription level of CX3CL1 m RNA in normoxic group was lower than that in hypoxia group and hypoxia+E2 group(P <0.05);the transcription level of CX3CL1 m RNA in hypoxia group was higher than that in hypoxia+E2 group,but the difference was not statistically significant(P >0.05);and the transcription level of CX3CR1 m RNA was detected: normoxic group <hypoxia+E2 <hypoxia group(P <0.05).3.CX3CL1 and CX3CR1 protein levels were detected by Western blot: normoxic group <hypoxia+E2 <hypoxia group(P <0.05).Conclusions:1.Hypoxia can promote the recruitment of alveolar macrophages in rats;2.17β-estradiol can reduce the recruitment of macrophages in a hypoxic environment;3.Under hypoxic environment,17β-estradiol may reduce the recruitment of macrophages by regulating the CX3CL1/CX3CR1 chemokine system.Part two Meta analysis of serum ADMA and pulmonary hypertensionObjective: To explore the correlation between serum ADMA level and the development and severity of pulmonary hypertension by meta-analysis.Methods:Search all the literature on the correlation between serum ADMA and PH in the database,and select according to the inclusion and exclusion criteria.Then the included studies were evaluated for NOS quality.Finally,Review Manager 5.3 software was used for meta-analysis to explore the correlation between serum ADMA and the occurrence,development and severity of PH.Results:This study finally included 10 articles,all of which explored the correlation between serum ADMA levels and the occurrence and development of PH.The meta-analysis results showed that serum ADMA was significantly higher in patients with PH than in those without PH(P <0.00001),but there was a high degree of heterogeneity among multiple studies;subgroup analysis was performed by different PH groups,and the results suggested heterogeneity in each group can be significantly reduced.There are two literatures that can be used to combine the data to explore the relationship between serum ADMA levels and PH severity.The results show that the level of serum ADMA is higher in patients with mild to moderate and severe PH than in those without PH(P <0.0001),and the PH of severe The serum ADMA was higher in patients with mild to moderate PH(P <0.00001).Two studies examined the value of serum ADMA levels in the follow-up of sildenafil treatment effects.The results of the combined data showed that serum ADMA levels after 6 months of sildenafil treatment were lower than before treatment(P <0.0001).Conclusions:Whether it is primary pulmonary hypertension or pulmonary hypertension secondary to other diseases,serum ADMA levels are significantly increased,and serum ADMA levels are positively correlated with the severity of pulmonary hypertension;In addition,serum ADMA levels can also reflect the therapeutic effect of sildenafil to a certain extent.Conclusions:1.In hypoxic environment,17β-estradiol may reduce the recruitment of macrophages by regulating the CX3CL1/CX3CR1 chemokine system,thereby alleviating pulmonary hypertension.CX3CL1/CX3CR1 chemokine system may be a potential therapeutic target.2.There is a correlation between serum ADMA level and PH,which may be a non-invasive biomarker to evaluate the occurrence and development of pulmonary hypertension,the monitoring of its severity,and the follow-up of treatment with sildenafil.