The transcriptomic profile shows the protective effects of celecoxib on cirrhotic splenomegaly

AbstractBackground Splenomegaly can exacerbate liver cirrhosis and portal hypertension. We have previously demonstrated that cyclooxygenase-2 (COX-2) inhibitor can attenuate cirrhotic splenomegaly. However, the mechanism of cirrhotic splenomegaly remains unclear, thus becoming the focus of the present study.Materials and methods Thioacetamide (TAA) intraperitoneal injection was used to induce cirrhotic splenomegaly. Rats were randomized into the control, TAA and TAA + celecoxib groups. Histological analysis and high-throughput RNA sequencing of the spleen were conducted. Splenic collagen III, α-SMA, Ki-67, and VEGF were quantified.Results A total of 1461 differentially expressed genes (DEGs) were identified in the spleens of the TAA group compared to the control group. The immune response and immune cell activation might be the major signaling pathways involved in the pathogenesis of cirrhotic splenomegaly. With its immunoregulatory effect, celecoxib presents to ameliorate cirrhotic splenomegaly and liver cirrhosis. Furthermore, 304 coexisting DEGs were obtained between TAA vs. control and TAA + celecoxib vs. TAA. Gene ontology (GO) and KEGG analyses collectively indicated that celecoxib may attenuate cirrhotic splenomegaly through the suppression of splenic immune cell proliferation, inflammation, immune regulation, and fibrogenesis. The impacts on these factors were subsequently validated by the decreased splenic Ki-67-positive cells, macrophages, fibrotic areas, and mRNA levels of collagen III and α-SMA.Conclusions Celecoxib attenuates cirrhotic splenomegaly by inhibiting splenic immune cell proliferation, inflammation, and fibrogenesis. The current study sheds light on the therapeutic strategy of liver cirrhosis by targeting splenic abnormalities and provides COX-2 inhibitors as a novel medical treatment for cirrhotic splenomegaly.Keywords: Spleentranscriptomic analysesliver cirrhosisinflammationfibrogenesis Author contributionsStudy concept and design: JG, ZH, and CT. Study supervision: JG, ZH, and CT. Investigation: ST, YY, YT, CZ, and ZH. Data analysis: ST and YY. Writing – original draft preparation: ST and YY. Writing – review and editing: ZH and JG.Ethical approvalAll the procedures performed in this study were approved by the Animal Use and Care Committee of West China Hospital and were conducted according to the regulations of West China Hospital.Consent formInformed consent was obtained from all individual participants included in the study.Disclosure statementThe authors report there are no competing interests to declare. All authors read and approved the final manuscript.Data availability statementAll the data are presented in the manuscript. All the data are available from the corresponding author Jinhang Gao upon reasonable request.Additional informationFundingThis work was supported by the National Natural Science Fund of China (82170623, 82170625, U1702281, 81873584, 82000613, 82000574, 82200687, and 82270649), the National Key R&D Program of China (2017YFA0205404), Sichuan Science and Technology Program (2020YJ0084, 2021YFS0147, and 2022NSFC0819), the 135 Projects for Disciplines of Excellence of West China Hospital, Sichuan University (ZYGD18004), the Natural Science Foundation of Chongqing (CSTB2022NSCQ-MSX0480), and Chongqing Science & Technology Bureau Research Project (CSTB2022BSXM-JCX0081).