The Role Of The Scavenger Receptor A In Cigarette Smoke Induced Chronic Obstructive Pulmonary Disease And Its' Pathogenic Mechanism In Leptospira Infection

Class A scavenger receptor SR-A is a pattern recognition receptor predominantly expressed on macrophages and can binds to a variety of ligands such as oxidized or acetylated LDL,bacterial lipopolysaccharide?LPS?,teichoic acid and double-stranded RNA.SR-A plays an important role in helping innate immune system recognize,phagocytize and clear pathogens.Besides host defense,SR-A plays an important role in various diseases,such as atherosclerosis and Alzheimer's disease,etc.The first part of this paper studies the role and mechanism of SR-A in smoking-induced COPD.The second part studies the molecular mechanism in the interaction between SR-A and Leptospira infection.Chronic obstructive pulmonary disease?COPD?is characterized by the destruction of the alveolar walls leading to permanent enlargement of distal respiratory air spaces.COPD is one of the leading causes on morbidity and mortality in the world.A major environmental causal factor is cigarette smoking,and genetic risk factors also play important roles on the occurrence of COPD.Genome-wide association studies showed that the variants of scavenger receptor SR-A was a risk factor for COPD susceptibility.However,it is still unclear what the roles of SR-A play in the pathogenesis of COPD.The first part of this paper is about COPD.Our study of COPD mouse model showed that SR-A knockout mice have more severe lung function damage and pulmonary emphysema than wild type mice.By measuring the level of lipid oxidation in lung homogenates,the lipid oxidation level in SR-A^-/-mice was significantly higher than that in WT mice.Correspondingly,expression of antioxidant gene in SR-A^-/-mice alveolar macrophages was significantly lower than in WT mice.This suggested that SR-A can inhibit the formation of COPD by improving oxidative stress in smokers.On cellular level?in vitro?,the peritoneal macrophages of WT and SR-A^-/-mice were stimulated with cigarette smoke extract?CSE?to analyze their lipid oxidation and antioxidant gene expression.The results showed that the level of lipid oxidation was higher and antioxidant gene expression of SR-A^-/-cells was lower than that of WT cells,which further demonstrated that SR-A can inhibit the oxidative stress induced by cigarette smoke.Above all,SR-A can inhibit the formation of COPD by promoting the oxidant/antioxidant balance.Leptospirosis is a global zoonotic disease caused by pathogenic leptospires.Human exposure to blood,urine and other contaminants from diseased animals may result in infection of the leptospira.The leptospires invade body through the mucosa or damaged skin.The Innate Immune system of host plays an important role in the defense of Leptospira infection.SR-A is an important type of scavenger receptor distributed on the surface of macrophages.However,it is not clear what roles SR-A plays in the Leptospira infection.In the second part of this paper,RAW264.7 mouse macrophage cell lines overexpressing SR-A were constructed and infected with Leptospira 56606v strain.The results showed that the phagocytosis of RAW264.7 cells overexpressing SR-A infected56606v strain were increased,SR-A can enhance macrophage phagocytosis of Leptospira 56606v strain.Our results also showed that Leptospira 56606v strain can survive in mouse peritoneal macrophages at 72h post infection.Correspondingly,Leptospira 56606v strain phagocytized by SR-A^-/-mouse peritoneal macrophages?PM?and survived in SR-A^-/-PM was fewer than WT PM.Infection of WT and SR-A^-/-mice by Leptospira 56606v strain?i.p?revealed that the Leptospira 56606v strain had less colonization in the liver and kidney of SR-A^-/-mice and showed slighter jaundice and hepatic injury compared to WT mice.Since the large number of Leptospira can survive in WT macrophages and spread to target organ for colonization,which may cause organ damage and aggravation of the disease.In conclusion,SR-A increases the phagocytosis of the Leptospira 56606v strain and results in more severe pathological damage in WT mice compare to the SR-A^-/-mice due to the higer load of Leptospira survive in macrophages and spread to target organ.