| Objective:Obstructive sleep apnea hypopnea syndrome(obstructive sleep apnea,OSA)of all-cause mortality and the risk of death increased obviously and can cause multi system and multi organ damage in population. Studies have shown that OSA is closely related to the occurrence of cardiovascular and cerebrovascular diseases,and is an independent risk factor for hypertension,coronary heart disease,left heart failure,pulmonary heart disease,myocardial infarction and stroke. OSA is a complex,multi factor and multi gene disorder. It is commonly believed that airway inflammation in OSA patients is caused by repeated mechanical damage associated with repeated intermittent collapse of the airways. Intermittent nocturnal hypoxia and ischemia / reperfusion injury can induce the production of oxygen free radicals,which can lead to airway inflammation and airway inflammation. Obstructive sleep apnea hypopnea syndrome(Obstructive Sleep Apnea,OSA)can cause all-cause mortality and the risk of death increased obviously and result in multi system and multi organ damages in the crowd[1, 2]. Several studies have shown that OSA is closely related to the occurrence of cardiovascular and cerebrovascular diseases,and is an independent risk factor for hypertension,coronary heart disease,left heart failure,pulmonary heart disease,myocardial infarction and stroke. OSA is a complex,multi factor and multi gene disorder. It is commonly believed that airway inflammation in OSA patients is caused by repeated mechanical damage associated with repeated intermittent collapse of the airways. Intermittent nocturnal hypoxia and ischemia / reperfusion injury can induce the production of oxygen free radicals,which can lead to the local inflammation of the airway and airway inflammation. Studies suggested that oxidative stress and proinflammatory cytokines in exhaled breath condensate in OSA were increased,and correlated with the severity of sleep apnea. There were some research on airway inflammation, but the lower respiratory tract inflammation associated with bronchial level research was rarely reported. Surfactant associated protein could regulate the function of inflammatory cell in respiratory system.The immune regulation of surfactant associated proteins includes inhibiting the activation of transcription factor、secretion of cytokine and the activation of human monocytes transcription factor NF-κB(NF-κB is an activator of ubiquitous transcription of inflammatory gene). In addition,the microbial composition of lower respiratory tract have the close relationship with health and disease,the microbial diversity and the relative abundance of the respiratory tract microbiota is significantly different between the state of lung disease severity and the health condition.We hypothesized that the local inflammatory in respiratory tract in OSA patients may also have changes in microbial community composition and abundance. Study the changes of surfactant associated protein and lower respiratory tract microbiota in patients with OSA which have the local airway inflammation and systemic inflammatory process changes has important significance in the study of the pathogenesis of OSA patients. This paper carried out a case-control study:1. The characteristics of OSA patients and its relationship between the sleep parameters and the factors in the local airway inflammation and systemic inflammation;2,the relationship between the sleep parameters of OSA and the pulmonary surfactant proteins both in serum and bronchoalveolar lavage fluid in OSA; 3, Changes in the relative abundance and composition of lower respiratory tract microbiota in OSA.Methods : This was a case-control study. All subjects according to the inclusion and exclusion criteria completed the all night polysomnography monitoring.We collected the related clinical data,the serum samples and the bronchoalveolar lavage specimens,evaluating the difference of each observation index between case group and control group. The first part:Evaluate the relationship between the levels of inflammatory factors tested by enzyme-linked immunosorbent assay and the sleep parameters in OSA. The second part:1、Evaluate the differences of surfactant proteins in serum and bronchoalveolar lavage fluid in the case group and the control group,observe the relationship between sleep parameters and serum surfactant protein in OSA.Observe the relationship between sleep parameters and the surface active proteins in serum and bronchoalveolar lavage fluid in the case group;observe the the relationship between surface active proteins in serum and bronchoalveolar lavage fluid.Observe the relationship between the various inflammatory factors in serum and bronchoalveolar lavage fluid with the surface active proteins in serum and bronchoalveolar lavage fluid,and the potential role in the OSA inflammatory pathway.Observe the correlation between sleep parameters and the surface active proteins in serum and bronchoalveolar lavage fluid in OSA.The third part : the 16 Sr RNA sequencing method : Determination the changes of the the lower respiratory tract microbiota between the case group and non OSA control group,comparing the changes in the microbial composition and abundance in the lower respiratory tract between the healthy people and Case group of OSA. And further confirmed that the inflammation in the lower respiratory tract plays an important role on the pathogenesis of OSA.Results:the first part:1,there has systemic inflammation in Obstructive sleep apnea. The levels of HIF-1α,Hs CRP,NF-κB cytokines TNF-α,IL-6 in the serum were increased,the levels of IL-6 in serum are correlated with the severity of OSA and independent of obesity. The inflammatory cytokines in bronchoalveolar lavage fluid in OSA were detected,and the elevated levels of HIF-1α,TNF-α,Hs CRP,NF-κB,IL-6 in the bronchoalveolar lavage fluid in OSA were positively related to the severity of OSA.The levels of IL-6,NF-κB,HIF-1α in the bronchoalveolar lavage fluid in OSA were positively correlated with the severity of OSA,and the same as BMI.increased with the aggravation of AHI in OSA. In addition,the levels of IL-6,IL-8,HIF-1α,and NF-κB in the alveolar lavage fluid in OSA were correlated with ODI3(events/hour)ODI4(events/hour). There was no significant correlation between the inflammatory factors in alveolar lavage fluid and Rs20kpa/l/s,and there was no significant correlation between the inflammatory factors in alveolar lavage fluid and MSa02(%),TST90,LSa02(%). In addition to Hs CRP,the levels of inflammatory factors in serum were positively correlated with the corresponding inflammatory factors in alveolar lavage fluid. In our study,there was no significant correlation between the protein level of Hs CRP and sleep apnea hypopnea indexes.Our study shows that the inflammation and oxidative stress in patients with OSA are not only a systematic response,but also have local responses in the local lower airways in OSA. The Increased levels of inflammatory cytokines such as IL-6、HIF-1α、NF-κB in BALF could be considered as signals of the the severity in OSA and these inflammatory cytokines could also be used to evaluate the prognosis of OSA. The second part:1,It confirmed that there was a statistically significant difference in the levels of pulmonary surfactant protein SP-A,SP-B and SP-D in serum in OSA compared with the control group.The levels of pulmonary surfactant protein SP-A,SP-B and SP-D in serum in OSA is significantly reduced;compared the relationship between the sleep parameters and the pulmonary surfactant protein SP-A,SP-B,SP-C,SP-D in Serum,there was a strong correlation between pulmonary surfactant protein SP-A,SP-B,SP-D in serum in OSA and AHI,and it is a negative correlation.It suggested that in OSA patients with the aggravated severity of the disease the levels of pulmonary surfactant protein SP-A,SP-B and SP-D in serum would decreased. 2,It confirmed that there were significant differences in the levels of SP-A、SP-B、SP-D in BALF between the OSA group and the control group. The levels of pulmonary surfactant protein SP-A,SP-B,SP-D in BALF were lower in OSA case group compared with the control group.The levels of SP-A. SP-B, SP-D in bronchoalveolar lavage fluid were negatively correlated with AHI and oxygen desaturation index(events/hour)of ODI3 and ODI4. Multiple linear regression analysis showed that there was significantly negative correlation between SP-A in bronchoalveolar lavage fluid and AHI in OSA related to the correlation between pulmonary surfactant proteins in bronchoalveolar lavage fluid and sleep parameters. 3,With the aggravated severity in patients with OSA,the levels of pulmonary surfactant proteins both in serum and bronchoalveolar lavage fluid may be decreased. 4,The level of SP-A、SP-B、SP-D in serum and bronchoalveolar lavage fluid were negatively correlated with the levels of HIF-1α,NF-κB,IL-6 in serum and bronchoalveolar lavage fluid.However,the level of SP-C in serum and bronchoalveolar lavage fluid was not correlated with the levels of HIF-1α、NF-κB,IL-6 in serum and bronchoalveolar lavage fluid. The third part:It could be done to analysize the abundance and composition of microbial flora in lung by bronchoalveolar lavage fluid. There has some changes in the microecological bacteria colony composition in the lower respiratory tract in OSA,but no significant changes in the diversity of microbial flora. and the abundance of Proteobacteria and Bacteroidetes bacteria increased. OSA may be a respiratory tract disease associated with chronic intermittent hypoxia and recurrent respiratory tract flora disorder and dysfunction. In OSA,the increased abundance of Proteobacteria and Bacteroidetes bacteria may cause the inflammation and immune response, which may lead to the aggravation of the disease.Conclusion:1、The changes of the levels of pulmonary surfactant proteins in the airway in patients with OSA may participate in the local airway inflammation and increased airway epithelial injury,cause airway resistance increased and form a vicious cycle in OSA,which will further elucidate the pathogenesis of OSA,also provide a new theoretical basis for the future clinical method of exogenous surfactant therapy in OSA. 2,There were no difference in the microbial composition in the lower respiratory tract between patients with OSA flora and healthy people,but the Proteobacteria,Bacteroidetes bacteria abundance changes.It may be correlated with gastroesophageal reflux,aspiration,chronic intermittent hypoxia and the airway inflammatory reaction. In the future,it would provide new ideas for prevention and control of OSA through the rational management of respiratory tract microbial flora. |
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