Introduction
Splenomegaly can exacerbate liver cirrhosis and portal hypertension. Thus, inhibiting splenomegaly may be a novel treatment for liver cirrhosis. We have previously demonstrated that cyclooxygenase-2 (COX-2) inhibitor can attenuate cirrhotic splenomegaly. However, the transcriptome profiles and precise pathogenesis of cirrhotic splenomegaly remain unknown, and few effective therapies are available. The role and mechanism of cyclooxygenase-2 (COX-2) in cirrhotic splenomegaly remain unclear.
Aims & Methods
Aims: We attempt to identify the transcriptomic profile of cirrhotic spleen, providing comprehensive valuable information for pathogenesis of splenomegaly. And to further validate the protective role of celecoxib on cirrhotic splenomegaly.
Methods: Thirty male Sprague-Dawley rats were randomized into the control group, TAA and TAA+Celecoxib groups. The control group: received intraperitoneal injection of normal saline (1ml, twice a week); the TAA group: received intraperitoneal injection of thioacetamide (TAA, 200 mg/kg, twice a week for 16 weeks); the TAA+celecoxib group: received TAA intraperitoneally and celecoxib via gastric gavage (20 mg/kg/day). Splenic gene profiling was analyzed by high-throughput RNA sequencing. Histological analysis of spleen tissue was evaluated by H&E, Sirius red, Prussian blue staining, and transmission electron microscopy. The splenic mRNA levels of collagen III and α-SMA and splenic contents of 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 can ameliorate cirrhotic splenomegaly and liver cirrhosis. Furthermore, 304 coexisting DEGs were obtained between TAA vs. control and TAA+celecoxib vs. TAA. According to GO and KEGG analyses, celecoxib may attenuate cirrhotic splenomegaly by suppressing splenic immune cell proliferation, inflammation, immune regulation, and fibrogenesis. The impacts of celecoxib on splenic immune cell proliferation, inflammation, immune regulation, and extracellular matrix were then validated by the decreased splenic Ki-67-positive cells, macrophages, fibrotic areas, and mRNA levels of collagen III and α-SMA.
Conclusion
Celecoxib attenuates cirrhotic splenomegaly by inhibiting splenic immune cell proliferation, inflammation, and fibrogenesis. The current study further validate that COX-2 inhibitors could serve as a novel medical treatment for cirrhotic splenomegaly based on transcriptomic analysis.