Physiology in Perspective: The New Normal-Life in a Pandemic.

As I write this editorial, it is now the second week in May, and most of us have been staying and working from home for nearly 2 months. The cost of the COVID-19 pandemic in human life is tragic, but all of us are impressed by the super heroes in healthcare, essential businesses, and public service who have stepped up despite the risk to themselves. Biomedical research has also stepped up to provide a better understanding of the pathophysiology of coronavirus (SARS-CoV-2) infection. For example, it now appears that COVID-19 symptoms are mediated in part by activation of the angiotensin II converting enzyme (ACE2) receptor, which is ubiquitous in many physiological systems, but especially in the cardiopulmonary system. For physiologists, it is interesting but frustrating that rats and mice are more resistant to SARS-CoV-2 infections and do not display any of the sometimes-fatal cardiopulmonary symptoms of COVID-19. The inefficient SARS-CoV-2 infection in mice and resistance in rats appears to be due to residue differences in their ACE2 receptors. Research in mice is now focusing on the impact of mutating the ACE2 receptor on susceptibility to SARS-CoV-2 infection rate, and perhaps later on disease symptoms and pathophysiological mechanisms of COVID-19. Of course, all of us are anticipating the successful development of a vaccine for COVID-19. Until then, we will continue to experience the new normal.

One of the major symptoms of COVID-19 is hypoxemia. Exposure to prolonged hypoxemia also occurs in disease conditions such as chronic obstructive lung disease (COPD) as well as life at high altitude. Chronic hypoxemia often leads to the development of pulmonary hypertension, a potentially life-threatening condition. In response to chronic hypoxia, the pulmonary vasculature undergoes several well-characterized changes; in particular, the vessel walls expand (i.e., thicken), and smooth muscle appears in typically non-muscular regions. Hyper-proliferation and enhanced migration of vascular wall cells in combination with the lack of apoptosis and appropriate cell turnover have been documented in animals and humans living at high altitude or with exposure to hypoxia in the laboratory setting. In her review (4), Shimoda discusses the intrinsic and extrinsic modulators contributing to this remodeling process. Over 65 million people have moderate to severe COPD, 140 million people worldwide live at high altitude, and more than 5 million people and counting have been infected with SARS-CoV-2. Further understanding of the precise cellular mechanisms involved in triggering or modulating the signaling pathways that promote pulmonary vascular cell growth during hypoxia should help to identify targets for novel therapies that can prevent, stop, and/or reverse the pulmonary vascular remodeling and ensuing pulmonary hypertension.

S-nitrosylation is the posttranslational modification of cysteine residues in proteins by nitric oxide (NO) to form S-nitrosothiols (SNO) and functions as a general signaling mechanism by altering the function of all classes of proteins. In the vasculature, SNOs serve as vasodilators, and S-nitrosylated hemoglobin in particular serves to circulate SNO vasodilatory activity in the mammalian respiratory cycle, i.e., hemoglobin carries three essential gases: O2, NO, and CO2. In their review, Premont and Stamler (3) discuss the link between SNO carriage by hemoglobin and adequate tissue oxygenation. The release of SNO from hemoglobin is proportional to the extent of hemoglobin deoxygenation, thus linking tissue hypoxia to tissue microvascular vasodilation and O2 delivery. Using a mouse model expressing human hemoglobin, or a mutant of β-globin cysteine-93 unable to be modified by SNO, cardiovascular phenotypes associated with hemoglobin S-nitrosylation and SNO delivery are being identified. These include the most important of all cardiovascular functions, basal tissue oxygenation, as well as hypoxia-induced tissue delivery, reactive hyperemia, protection from ischemic and pressure-overload cardiac injuries, and regulation of breathing. All of these phenotypes occur despite clear compensatory changes in erythrocytes—where SNO accumulates on additional sites on hemoglobin that are not associated with allosteric transition (i.e., not hypoxia regulated) and on low-molecular-weight thiols—and in tissues themselves, which grow new blood vessels. The phenotypes seen in these mutant mice correspond to physiological and pathophysiological effects noted in normal humans and in patients with diseases associated with tissue hypoxia, including high-altitude sickness, peripheral arterial disease, pulmonary hypertension, sickle cell anemia, and now possibly COVID-19. Mouse studies also suggest critical roles in human ischemic heart disease and heart failure. Drugs designed to augment hemoglobin S-nitrosylation, specifically at βCys93, are being tested for their ability to improve O2 delivery following transfusion of stored blood (which loses SNO) and have the potential to improve directly O2 delivery to hypoxic tissues in myriad diseases. Collectively, these studies suggest that the mammalian respiratory cycle is a three-gas system and that delivery of SNO by red blood cells is essential for microvascular blood flow that oxygenates all tissues.

While the world focuses on the viral pandemic of COVID-19, other microorganisms also cause significant morbidity and mortality. Entamoeba histolytica, a protozoan parasite with high prevalence in developing countries, infects 50 million people worldwide. E. histolytica causes amoebiasis, a disease affecting the intestine and the liver. It is the third leading cause of human deaths among parasitic infections. Establishing an amoebic infection involves several crucial steps, such as adherence to the intestinal epithelium, invasion into the tissues, and dissemination to other organs. Once amoebas invade the tissues, they have to survive in the host by evading the immune system. In their review (5), Uribe-Querol and Rosales discuss the general pathogenic factors of E. histolytica, and how these factors participate in establishing infection. They also discuss the immune response, particularly the role of inflammation and the participation of neutrophils, during amoebiasis. Research on E. histolytica-induced amoebiasis is relevant to several aspects of human physiology, including the interaction of protozoan parasites with the digestive system and the role of the immune system in preventing the onset of amoebiasis. In addition, a better understanding of how amoebas are transmitted and how amoebiasis is diagnosed and treated has the potential to improve the daily life of people living in E. histolytica endemic areas of the world.

The gut microbiota is a recent new player in the pathophysiology of both intestinal and extra-intestinal diseases. The gut and the liver have bidirectional communication via the biliary system and the portal vein. It is this communication that leads to the liver being affected by gut dysbiosis. Various liver diseases, such as alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and cholestatic liver diseases, have been associated with altered gut microbiome. In their review (1), Jiang and Schnabl discuss the role of gut microbiome and microbial products in liver diseases. Current research on gut microbiota suggests that microbial factors are driving forces in many diseases. Manipulating microbiome through common approaches such as fecal microbial transplantation and pre- and probiotics treatments provides new insights into liver disease therapy. Further preclinical and clinical studies in this area of research may lead to more accurate diagnostic tools and more effective therapies for liver diseases.

The gut microbiota produces metabolites that can be absorbed into the blood stream and influence host proteins at distant sites. Gut dysbiosis (shifts in the gut microbiota) in humans and animal models plays a key role in blood pressure regulation. Known gut microbial metabolites, which influence blood pressure and cardiovascular function, include short chain fatty acids (SCFAs), which can signal via G-protein-coupled receptors, and trimethylamine-N oxide (TMAO). In their review (2), Poll and colleagues discuss specific gut microbial metabolites that are reported to influence blood pressure regulation. Hypertension itself may induce changes in gut microbiota, and these changes may then serve to further drive hypertension. Furthering the knowledge of the mechanisms underlying host-microbe communications should lead to a better understanding of how microbial metabolites influence the host, and how changes in host physiology result in remodeling of the gut microbiota, perhaps leading to novel therapies to treat hypertension.