TWIRLS, an automated topic-wise inference method based on massive literature, suggests a possible mechanism via ACE2 for the pathological changes in the human host after coronavirus infection

Xiaoyang Ji; Chunming Zhang; Yubo Zhai; Zhonghai Zhang; Yiqing Xue; Chunli Zhang; Guangming Tan; Gang Niu

Pro-inflammatory cytokines derived from immune cells normally regulate the RAS component, which further accelerates the formation of systemic and local Ang II [28] [29] [30] . In particular, pro-inflammatory cytokines regulate the production of AGT in the liver and kidney [31] [32] [33] . On the other hand, RAS has also been implicated in mediating the cytokine storm and has functional relationships with the immune system. Angiotensin II regulates vascular tension and stimulates the release of pro-inflammatory cytokines [34, 35] . The production and release of CXC chemokines can induce the accumulation of neutrophils in vivo [36] . Meanwhile, ACE inhibitors and Ang II receptor blockers have been used in a number of cytokine-mediated inflammatory pathologies, and AT1R blockers (angiotensin receptor blocker) were shown to have beneficial effects that were commonly attributed to AT2R activation [37] . At the same time, it was reported that Ang II-stimulated human endothelial cells had increased release of a CXC chemokine, IP-10. The IFN-γ-inducible protein 10 (IP-10 or CXCL10) is mainly expressed in the lung and is a chemoattractant for activated T cells. The expression of IP-10 has been observed in many Th1-type inflammatory diseases, where it is thought to play an important role in recruiting activated T cells to sites of tissue inflammation. Therefore, RAS dysfunction may result in the accumulation of cytokines, such as in the lungs leading to excessive accumulation of immune cells and interstitial fluid, blocking the airways and causing eventual death. As reported in the first severely infected patients diagnosed with COVID-19, a large number of patients experienced "cytokine storms" that was fatal [7] . Figure 6 summarizes the functional changes and pathological consequences of RAS system after ACE2 combines with the coronavirus.