Physiology Of Gastrointestinal Tract Pdf REPACK Download
It can be assumed that increased ACE2 expression or the co-expression at high levels of the ACE2, TMPRSS2 and CTSB/L proteins in SARS-CoV-2 targeted cells/tissues will correlate with higher risk of viral infection. Reportedly, the ACE2, TMPRSS2 and CTSB/L genes/proteins are widely expressed in human tissues; being particularly enriched in kidney, heart, as well as in tissues of the respiratory and gastrointestinal tract . The ACE2 and TMPRSS2 genes are minimally expressed in blood cells and tend to be co-regulated ; it was also found that the SARS-CoV-2 entry factors are expressed at high levels in nasal epithelial cells . These observations suggest that even in the absence of underlying co-morbidities most vital human organs are potentially vulnerable to SARS-CoV-2 infection. It was also found that the ACE2/TMPRSS2 genes are (among others) downregulated by tumor necrosis factor (TNF) and are induced by several pro-inflammatory conditions including Barrett's esophagus, gastric infection by Helicobacter pylori, obesity, diabetes, autoimmune diseases, as well as by viral infections, cigarette smoking, growth factors, interferons (IFNs) and androgens . In support, ACE2 expression was stimulated by a type I Interferon (IFN-a) gene in human airway epithelial cells  and thus, SARS-CoV-2 could (indirectly) exploit IFN-driven upregulation of ACE2 to enhance infection rate in target tissues.
Physiology Of Gastrointestinal Tract Pdf Download
In line with these notions, the enrichment of all SARS-CoV-2 infection-related cellular modules (i.e., ACE2, TMRSS2 and CTSB, CTSL) in the gastrointestinal tract [17, 36] explain diarrhea as a major symptom of COVID-19 and SARS-CoV-2 RNA isolation from stool [33, 37, 38] (Fig. 2b). Given that SARS-CoV-2 productively infects human gut enterocytes  or human intestinal organoids  it is plausible that human intestinal tract represents a major entry and replication site for SARS-CoV-2 due to consumption of contaminated food. In support, intra-gastric inoculation of SARS-CoV-2 in a mouse model expressing human ACE2 caused productive infection and most interestingly led to pulmonary pathological changes . A significant association between liver dysfunction and mortality of COVID-19 patients has been also reported [41, 42], which may relate to direct viral infection (still questionable due to relatively low ACE2 expression levels in the liver ); to indirect damage because of drug-induced liver injury or because of COVID-19-triggered systemic inflammation . Analyses of severe COVID-19-induced biochemical alterations in the liver have shown the elevation of liver enzymes, such as alanine aminotransferases and aspartate aminotransferases, and significantly lower albumin levels [43, 44] and thus, liver markers should be monitored continuously during COVID-19 evolvement. ACE2 and TMPRSS2 are highly expressed in gallbladder , whereas regarding pancreas ACE2 is expressed in exocrine tissue microvasculature and in a subset of pancreatic ducts with TMPRSS2 expression being restricted to ductal cells [45, 46]. Notably, both ACE2 and TMPRSS2 are rarely expressed in single pancreatic β cells from donors with or without diabetes [45, 46] suggesting that SARS-CoV-2 cannot directly infect β cells.
Conclusively, regarding primary sites of SARS-CoV-2 infection although lungs (Fig. 2a) and likely the gastrointestinal tract (Fig. 2b) are grounds zero during the infection process, SARS-CoV-2 and/or COVID-19 also tear multiple organ systems, with major targets (because of high ACE2, TMPRSS2 expression) being the heart and kidneys.
Given the aforementioned sequence of events, tissues affected and downstream pathologies, the design of COVID-19 therapeutics (until the discovery of an effective highly specific anti-viral drug and/or a vaccine) may be complex, but it also presents with several potentially druggable opportunities. Overall, it is now understood that acute COVID-19 is a two-phase disease, including (a) infection and spreading of the virus mainly in the respiratory and gastrointestinal tracts, and, (b) ARDS (which can occur after a temporal improvement) and the uncontrolled immune response of the host  which can then lead to worsening of ARDS, development of multi-organ pathologies and systemic failure (Fig. 2) . Effective therapeutic treatments should thus probe both SARS-CoV-2 inhibition through better understanding of its life cycle and also the side-effects induced by COVID-19 due to immune system overactivation and organ dysfunction caused by the broad organotropism of SARS-CoV-2.
Autopsies of SARS patients showed that SARS-CoV infection can cause injury to multiple organs, such as the heart, kidney, liver, skeletal muscle, central nervous system, and adrenal and thyroid glands, besides the lungs [30, 31]. Most critically ill patients with COVID-19 also had multiple organ damage, including acute lung injury, acute kidney injury, cardiac injury, liver dysfunction, and pneumothorax . As with SARS and COVID-19, organ injury is also frequently observed in MERS, especially the gastrointestinal tract and kidneys, while the incidence of acute cardiac injury is less common [33,34,35,36]. Unlike SARS-CoV and SARS-CoV-2, MESR-CoV uses DPP4 as its entry receptor, which is mainly expressed on pneumocytes, multinucleated epithelial cells, and bronchial submucosal gland cells of the lungs; epithelial cells of the kidney and small intestine; and activated leukocytes [37,38,39]. DPP4 is not abundantly expressed on myocardial cells [37,38,39]. Therefore, this indicates that organ involvement and injury is strongly associated with receptor distribution in the body.
The gastrointestinal tract, especially the intestine, is vulnerable to SARS-CoV and SARS-CoV-2 infections. SARS-CoV particles have been detected in epithelial cells of the intestinal mucosa, but not in the esophagus and stomach [30, 42]. The main pathological finding in the intestines of patients with SARS was the depletion of mucosal lymphoid tissue . Only mild focal inflammation was detected in the gastrointestinal tract . These findings may explain why gastrointestinal manifestations in COVID-19 are not severe and are transient.
Mast cells are immune cells of the myeloid lineage and are present in connective tissues throughout the body. The activation and degranulation of mast cells significantly modulates many aspects of physiological and pathological conditions in various settings. With respect to normal physiological functions, mast cells are known to regulate vasodilation, vascular homeostasis, innate and adaptive immune responses, angiogenesis, and venom detoxification. On the other hand, mast cells have also been implicated in the pathophysiology of many diseases, including allergy, asthma, anaphylaxis, gastrointestinal disorders, many types of malignancies, and cardiovascular diseases. This review summarizes the current understanding of the role of mast cells in many pathophysiological conditions.
In addition to the abovementioned organs, it is known that the functions of the cardiovascular system, gastrointestinal tract, and central nervous system are often impaired during sepsis and are crucial for patient outcome. Although some therapies, including beta-blockers for the cardiovascular system, early enteral nutrition for the gastrointestinal tract, and light sedation/early rehabilitation for the central nervous system, are potentially effective, their efficacy is limited. Consequently, new organ-specific strategies based on a novel insight into the pathophysiology should be explored. 350c69d7ab