Comprehensive Physiology最新文献

The lung is an inherently mechanosensitive organ, where cells of the airway and parenchyma experience a range of mechanical forces throughout life including shear, stretch, and compression, in both health and disease. In this regard, pediatric and adult lung diseases such as wheezing and asthma, bronchopulmonary dysplasia (BPD), chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis (PF) all involve macroscopic and cellular changes to the mechanical properties of the bronchial airways and/or parenchyma to varying extents. Accordingly, understanding how mechanical forces are sensed in the lung, and the responses of cells and tissues in the context of normal development and health versus disease conditions becomes highly relevant. There is increasing recognition that transduction of mechanical forces into cellular responses involves a number of channels, some of which are inherently mechanosensitive. Such channels trigger mechanotransduction pathways that may further mediate cellular remodeling, inflammation, and other pathophysiologic mechanisms in response to stretch, stiffness, and inflammatory cascades. Two particularly important channel families have emerged in pulmonary pathophysiology: the transient receptor potential vanilloid family with focus on member TRPV4 and the recently identified Piezo (PZ) channels. Here, we explore current understanding of the contributions of TRPV4 and PZ channels in lung health and disease states, focusing on the interactions between these mechanosensitive channels and their local environment including immune cells, the extracellular matrix, and cellular cytoskeletal elements. We further discuss potential areas for future research to better understand the impact of mechanical channels on pulmonary health and disease. © 2023 American Physiological Society. Compr Physiol 13:5157-5178, 2023.

Although it is most well-known for its roles in central nervous system (CNS) function, the vast majority of serotonin, or 5-hydroxytryptamine (5-HT), is produced in the gastrointestinal (GI) tract. 5-HT is synthesized mostly by enterochromaffin (EC) cells of the GI epithelium and, in small part, by neurons of the enteric nervous system (ENS). The GI tract contains an array of broadly distributed 5-HT receptors, which participate in functions such as motility, sensation, inflammation, and neurogenesis. The roles of 5-HT in these functions are reviewed, as well as its role in the pathophysiology of disorders of gut-brain interaction (DGBIs) and inflammatory bowel diseases (IBD). © 2023 American Physiological Society. Compr Physiol 13:4851-4868, 2023.

Over the past two decades, with the advent and adoption of highly active anti-retroviral therapy, HIV-1 infection, a once fatal and acute illness, has transformed into a chronic disease with people living with HIV (PWH) experiencing increased rates of cardio-pulmonary vascular diseases including life-threatening pulmonary hypertension. Moreover, the chronic consequences of tobacco, alcohol, and drug use are increasingly seen in older PWH. Drug use, specifically, can have pathologic effects on the cardiovascular health of these individuals. The "double hit" of drug use and HIV may increase the risk of HIV-associated pulmonary arterial hypertension (HIV-PAH) and potentiate right heart failure in this population. This article explores the epidemiology and pathophysiology of PAH associated with HIV and recreational drug use and describes the proposed mechanisms by which HIV and drug use, together, can cause pulmonary vascular remodeling and cardiopulmonary hemodynamic compromise. In addition to detailing the proposed cellular and signaling pathways involved in the development of PAH, this article proposes areas ripe for future research, including the influence of gut dysbiosis and cellular senescence on the pathobiology of HIV-PAH. © 2023 American Physiological Society. Compr Physiol 13:4659-4683, 2023.

Inflammatory bowel disease (IBD) is an idiopathic disease of disordered chronic inflammation in the intestines that affects many people across the world. While the disease is still being better characterized, greater progress has been made in understanding the many components that intersect in the disease. Among these components are the many pieces that compose the intestinal epithelial barrier, the various cytokines and immune cells, and the population of microbes that reside in the intestinal lumen. Since their discovery, the hypoxia-inducible factors (HIFs) have been found to play an expansive role in physiology as well as diseases such as inflammation due to their role in oxygen sensing-related gene transcription, and metabolic control. Making use of existing and developing paradigms in the immuno-gastroenterology of IBD, we summarized that hypoxic signaling plays as another component in the status and progression of IBD, which may include possible functions at the origins of inflammatory dysregulation. © 2023 American Physiological Society. Compr Physiol 13:4767-4783, 2023.

Impaired glucose tolerance (IGT) and β-cell dysfunction in insulin resistance associated with obesity lead to type 2 diabetes (T2D). Glucose-stimulated insulin secretion (GSIS) from β-cells occurs via a canonical pathway that involves glucose metabolism, ATP generation, inactivation of K _ATP channels, plasma membrane depolarization, and increases in cytosolic concentrations of [Ca ²⁺ ] _c . However, optimal insulin secretion requires amplification of GSIS by increases in cyclic adenosine monophosphate (cAMP) signaling. The cAMP effectors protein kinase A (PKA) and exchange factor activated by cyclic-AMP (Epac) regulate membrane depolarization, gene expression, and trafficking and fusion of insulin granules to the plasma membrane for amplifying GSIS. The widely recognized lipid signaling generated within β-cells by the β-isoform of Ca ²⁺ -independent phospholipase A ₂ enzyme (iPLA ₂ β) participates in cAMP-stimulated insulin secretion (cSIS). Recent work has identified the role of a G-protein coupled receptor (GPCR) activated signaling by the complement 1q like-3 (C1ql3) secreted protein in inhibiting cSIS. In the IGT state, cSIS is attenuated, and the β-cell function is reduced. Interestingly, while β-cell-specific deletion of iPLA ₂ β reduces cAMP-mediated amplification of GSIS, the loss of iPLA ₂ β in macrophages (MØ) confers protection against the development of glucose intolerance associated with diet-induced obesity (DIO). In this article, we discuss canonical (glucose and cAMP) and novel noncanonical (iPLA ₂ β and C1ql3) pathways and how they may affect β-cell (dys)function in the context of impaired glucose intolerance associated with obesity and T2D. In conclusion, we provide a perspective that in IGT states, targeting noncanonical pathways along with canonical pathways could be a more comprehensive approach for restoring β-cell function in T2D. © 2023 American Physiological Society. Compr Physiol 13:5023-5049, 2023.

Renal function increases in pregnancy due to the significant hemodynamic demands of plasma volume expansion and the growing feto-placental unit. Therefore, compromised renal function increases the risk for adverse outcomes for pregnant women and their offspring. Acute kidney injury (AKI), or sudden loss of kidney function, is a significant event that requires aggressive clinical management. An AKI event in pregnancy, or in the postpartum period, significantly increases the risk of adverse pregnancy events and fetal and maternal mortality. At present, there are significant clinical challenges to the identification, diagnosis, and management of pregnancy-associated AKI due to changing hemodynamics in pregnancy that alter baseline values and to treatment limitations in pregnancy. Emerging data indicate that patients that are considered clinically recovered following AKI, which is currently assessed primarily by return of plasma creatinine levels to normal, maintain risk of long-term complications indicating that current recovery criteria mask the detection of subclinical renal damage. In association, recent large-scale clinical cohorts indicate that a history of AKI predisposes women to adverse pregnancy events even years after the patient is considered recovered from AKI. Mechanisms via which women develop AKI in pregnancy, or develop adverse pregnancy events post-AKI, are poorly understood and require significant study to better prevent and treat AKI in women. © 2023 American Physiological Society. Compr Physiol 13:4869-4878, 2023.

Microbiomes include bacteria, viruses, fungi, and other microbes. The microbiome modulates numerous aspects of host physiology and is critical in the pathophysiology of diseases, including colon cancer. Although gut bacterial pathogenesis has become an emerging area in colon cancer, the multi-kingdom aspect of microbiome has yet to be explored. Similar to the bacterial component of the microbiome, the virome contains certain makeup that varies between individuals. In the current review, we introduce the concepts of microbiome and microbiota, research history, methods for modern microbiome studies, and recent progress of mechanisms responsible for microbiome and virome in colon cancer. Furthermore, we discuss our understanding of microbial metabolites in the disease development and therapy of colon cancer. Finally, the gut microbiota can affect the efficacy and toxicity of cancer therapy. We discuss the challenges and future perspectives in microbiome and colon cancer. Exploring and understanding the mechanisms of microbiome will provide insights into effective approaches in potential prevention of treatment of colon cancer. © 2023 American Physiological Society. Compr Physiol 13:4685-4708, 2023.

Extracellular vesicles (EVs) are membrane-bound nanoparticles released by cells and are an important means of intercellular communication in physiological and pathological states. We provide an overview of recent advances in the understanding of EV biogenesis, cargo selection, recipient cell effects, and key considerations in isolation and characterization techniques. Studies on the physiological role of EVs have relied on cell-based model systems due to technical limitations of studying endogenous nanoparticles in vivo . Several recent studies have elucidated the mechanistic role of EVs in liver diseases, including nonalcoholic fatty liver disease, viral hepatitis, cholestatic liver disease, alcohol-associated liver disease, acute liver injury, and liver cancers. Employing disease models and human samples, the biogenesis of lipotoxic EVs downstream of endoplasmic reticulum stress and microvesicles via intracellular activation stress signaling are discussed in detail. The diverse cargoes of EVs including proteins, lipids, and nucleic acids can be enriched in a disease-specific manner. By carrying diverse cargo, EVs can directly confer pathogenic potential, for example, recruitment and activation of monocyte-derived macrophages in NASH and tumorigenicity and chemoresistance in hepatocellular carcinoma. We discuss the pathogenic role of EVs cargoes and the signaling pathways activated by EVs in recipient cells. We review the literature that EVs can serve as biomarkers in hepatobiliary diseases. Further, we describe novel approaches to engineer EVs to deliver regulatory signals to specific cell types, and thus use them as therapeutic shuttles in liver diseases. Lastly, we identify key lacunae and future directions in this promising field of discovery and development. © 2023 American Physiological Society. Compr Physiol 13:4631-4658, 2023.

The sympathetic nervous system (SNS) is a crucial arm of the peripheral nervous system (PNS) and includes catecholaminergic neurons that release norepinephrine (NE) onto numerous effector tissues and organs in the body. SNS innervation of both white (WAT) and brown adipose tissue (BAT) is clearly essential for proper tissue function and metabolic control, as decades of surgical, chemical, and genetic denervation studies have demonstrated. Despite our vast knowledge about adipose sympathetic innervation, especially in the context of cold-stimulated browning and thermogenesis that are under SNS control, newer data now provide a nuanced view of the SNS supply to adipose, including its regulation by local neuroimmune cells and neurotrophic factors, the co-release of modulatory neuropeptides along with NE, the importance of local SNS drive to adipose versus systemic increases in circulating catecholamines, and the long-overlooked interplay between adipose sympathetic and sensory nerves. This article brings a modern view to the regulation of sympathetic innervation patterns in WAT and BAT, how to image and quantify the nerve supply, contributions of adipose SNS to tissue functions, and how adipose tissue nerves respond to tissue remodeling and plasticity with changing energy demands. © 2023 American Physiological Society. Compr Physiol 13:4985-5021, 2023.

Heart transplantation (HT) is one of the prodigious achievements in modern medicine and remains the cornerstone in the treatment of patients with advanced heart failure. Advances in surgical techniques, immunosuppression, organ preservation, infection control, and allograft surveillance have improved short- and long-term outcomes thereby contributing to greater clinical success of HT. However, prolonged allograft and patient survival following HT are still largely restricted by the development of late complications, including allograft rejection, infection, cardiac allograft vasculopathy (CAV), and malignancy. The introduction of mTOR inhibitors early after HT has demonstrated multiple protective effects against CAV progression, renal dysfunction, and tumorigenesis. Therefore, several HT programs increasingly use mTOR inhibitors with partial or complete withdrawal of calcineurin inhibitor (CNI) in stable HT patients to reduce complications risk and improve long-term outcomes. Furthermore, despite a substantial improvement in exercise capacity and health-related quality of life after HT as compared to advanced heart failure patients, most HT recipients remain with a 30% to 50% lower peak oxygen consumption (Vo ₂ ) than that of age-matched healthy subjects. Several factors, including alterations in central hemodynamics, HT-related complications and alterations in the musculoskeletal system, and peripheral physiological abnormalities, presumably contribute to the reduced exercise capacity following HT. Cardiac denervation and subsequent loss of sympathetic and parasympathetic regulation are responsible for various physiological alterations in the cardiovascular system, which contributes to restricted exercise tolerance. Restoration of cardiac innervation may improve exercise capacity and quality of life, but the reinnervation process is only partial even several years after HT. Multiple studies have shown that aerobic and strengthening exercise interventions improve exercise capacity by increasing maximal heart rate, chronotropic response, and peak Vo ₂ after HT. Novel exercise modalities, such as high-intensity interval training (HIT), have been proven as safe and effective for further improvement in exercise capacity, including among de novo HT recipients. Further developments have recently emerged, including donor heart preservation techniques, noninvasive CAV and rejection surveillance methods, and improvements in immunosuppressive therapies, all aiming at increasing donor availability and improving late survival after HT. © 2023 American Physiological Society. Compr Physiol 13:4719-4765, 2023.