Dual Roles Of USP10 In Acute Lung Injury And Pulmonary Fibrosis

The Corona Virus Disease 2019（COVID-19）caused by New Coronavirus（SARS-Co V-2）targets many tissues/organs,but mainly leads to acute lung injury（ALI）and its more severe form,acute respiratory distress syndrome（ARDS）.At present,the acute pneumonia caused by the virus is still under control and has claimed many lives in the world.Exploring new therapeutic targets of acute pneumonia and pulmonary fibrosis is imperative for the development of more effective therapy of the COVID-19 patients.Ubiquitination is an enzymatic cascade that requires the orchestrated interplay of three different ubiquitin enzymes,and plays an indispensable role in maintaining physiological functions.Deubiquitination,the reversal of ubiquitination process,is also of critical importance in physiological processes.To explore the function of USP10 in ALI,we first established a mouse model of ALI by endotracheal instillation of lipopolysaccharide（LPS）.We found that the expression of USP10 in the lung of ALI mice was significantly decreased.To further explore the function of USP10 and its mechanism in ALI,we generated USP10 flox mice and bred them with a universal expressed Cre ERT2 driver line(UBC-Cre^ERT2or SFTPC-Cre^ERT2),we confirmed that UBC-Cre^ERT2;USP10^f/f mice could effectively ablate USP10 expression in the lung upon tamoxifen induction.Interestingly we discovered that,compared to the UBC-Cre^ERT2 control mice,LPS-induced ALI was significantly improved in UBC-Cre^ERT2;USP10^f/f mice.To explore the role of USP10in pulmonary fibrosis,we further constructed a pulmonary fibrosis mouse model using LPS or bleomycin induction for 21 days.The results showed that,compared to SFTPC-Cre^ERT2control mice,the body weight of SFTPC-Cre^ERT2;USP10^f/f mice recovered much slower,and the proportion of dead space was larger,indicating that the extend of fibrosis was more serious after USP10 knockout,which is likely caused by the decline of AT2 proliferation based on our preliminary analysis.Ongoing and future study will further address the role of USP10 in the disease pathology as well as its mechanism of action in these mice and the injury models.In conclusion,USP10 may play different roles in acute lung injury and pulmonary fibrosis is firstly reported in the world.On the one hand,LPS-induced ALI was improved in USP10 knockout mice,on the other hand,USP10 knockout in AT2 increase the degree of pulmonary fibrosis induced by LPS or bleomycin.The new discovery provides a potential target for the treatment of ALI and pulmonary fibrosis.