Effects And Mechanism Of Short Chain Fatty Acids On Lipopolysaccharide Induced Acute Respiratory Distress Syndrome In Rats

Objective:By observing the effects of short chain fatty acids（SCFAs）on lipopolysaccharide（LPS）-induced acute respiratory distress syndrome（ARDS）rats,and studying the role of MAPK and NF-κB signaling pathway in the procrss,to investigate the effects and possible intervention mechanism of SCFAs on ARDS.Methods:Twenty male SD rats were randomly divided into control group,model group（ARDS group）,low-dose SCFAs group and high-dose SCFAs group,and received normal saline（NS）,NS,low-dose SCFAs（sodium acetate300mg/kg,sodium propionate 100mg/kg,sodium butyrate 100mg/kg）and high-dose SCFAs（sodium acetate 600mg/kg,sodium propionate 200mg/kg,sodium butyrate 200mg/kg）respectively by gavage for 7 days（once a day）.At the end of the intervention,rats in the control group were perfused with NS,and the remaining groups were perfused with LPS（5 mg/kg）to establish a rat ARDS model.The rats were killed 12 hours after modeling,and the partial pressure of oxygen（Pa O₂）in the abdominal aorta and the water content of the right lung tissue（expressed as wet/dry weight,namely W/D）were detected.HE staining was used to observe the tissue of the upper lobe of the left lung in rats,pathological sections were used to evaluate the degree of lung injury.ELISA was used to detect the concentrations of pro-inflammatory/anti-inflammatory factors TNF-α,IL-6 and IL-10 in arterial serum and bronchoalveolar lavage fluid（BALF）.Western bloting was used to detect MAPK and NF-κB signaling pathway JNK,p-JNK,ERK,p-ERK,p38 MAPK,p-p38 MAPK,NF-κB p65,p-NF-κB p65（p means phosphorylation）protein expression of the left lower lobe tissue,and immunohistochemistry（IHC）was used to detect the expression of tight junction proteins ZO-1 and Occludin in colon.Results:Compared with the control group,the respiration of ARDS rats in the model group was inhibited,manifested as the decrease of Pa O₂,extensive edema occurred and W/D increased in lung tissue,damage to the alveolar structure and infiltration of inflammatory cells of lung pathological section could be observed under the microscope,and the score of lung injury increased.The concentrations of pro-inflammatory factors TNF-αand IL-6 in serum and BALF increased significantly,and the level of anti-inflammatory factor IL-10increased.The protein expression of p-JNK,p-ERK,p-p38 MAPK,p-NF-κB p65 in lung tissue was significantly increased,while immunohistochemistry of the colon tissue showed that the expression of intestinal barrier structural proteins ZO-1 and Occludin was significantly decreased（all P<0.05）.Compared with the rats in the model group,Pa O₂increased,W/D decreased,and the degree and score of lung pathological injury decreased in the low-dose and high-dose SCFAs groups,and the inflammatory factor TNF-αand IL-6 in serum and BALF decreased,the concentration of anti-inflammatory factor IL-10 increased significantly.The relative expression of p-JNK,p-ERK,p-p38MAPK,p-NF-κB p65 protein in lung tissue decreased,while the expression of ZO-1 and Occludin protein increased in colon tissue sections（all P<0.05）.Compared with the low-dose SCFAs group,the above-mentioned indexes in the high-dose SCFAs group was improved more significantly（all P<0.05）.Conclusion:SCFAs has a wide range of functions and has been proved to affect the immune and inflammatory responses in the gut and the whole body through a variety of ways.Intestinal supplementation of SCFAs could effectively alleviated ARDS induced by LPS intratracheal perfusion in rats.Its mechanism may be related to enhancing the intestinal epithelial cell barrier,inhibiting the phosphorylation of MAPK and NF-κB signaling pathway proteins,thereby reducing the release of downstream pro-inflammatory factors TNF-αand IL-6,and increasing the production of anti-inflammatory factors IL-10.