Comprehensive Physiology最新文献

Heart failure is a clinical syndrome characterized by the inability of the cardiovascular system to provide adequate cardiac output at normal filling pressures. This results in a clinical syndrome characterized by dyspnea, edema, and decreased exertional tolerance. Heart failure with preserved ejection fraction (HFpEF) is an increasingly common disease, and the incidence of HFpEF increases with age. There are a variety of factors which contribute to the development of HFpEF, including the presence of hypertension, diabetes, obesity, and other pro-inflammatory states. These comorbid conditions result in changes at the biochemical and cell signaling level which ultimately lead to a disease with a great deal of phenotypic heterogeneity. In general, the physiologic dysfunction of HFpEF is characterized by vascular stiffness, increased cardiac filling pressures, pulmonary hypertension, and impaired volume management. The normal and abnormal processes associated with aging serve as an accelerant in this process, resulting in the hypothesis that HFpEF represents a form of presbycardia. In this article, we aim to review the processes importance of aging in the development of HFpEF by examining the disease and its causes from the biochemical to physiologic level. © 2022 American Physiological Society. Compr Physiol 12: 1-10, 2022.

Physiological function fluctuates across 24 h due to ongoing daily patterns of behaviors and environmental changes, including the sleep/wake, rest/activity, light/dark, and daily temperature cycles. The internal circadian system prepares the body for these anticipated behavioral and environmental changes, helping to orchestrate optimal cardiovascular and metabolic responses to these daily changes. In addition, circadian disruption, caused principally by exposure to artificial light at night (e.g., as occurs with night-shift work), increases the risk for both cardiovascular and metabolic morbidity and mortality. Regular exercise is a countermeasure against cardiovascular and metabolic risk, and recent findings suggest that the cardiovascular benefits on blood pressure and autonomic control are greater with evening exercise compared to morning exercise. Moreover, exercise can also reset the timing of the circadian system, which raises the possibility that appropriate timing of exercise could be used to counteract circadian disruption. This article introduces the overall functional relevance of the human circadian system and presents the evidence surrounding the concepts that the time of day that exercise is performed can modulate the cardiovascular and metabolic benefits. Further work is needed to establish exercise as a tool to appropriately reset the circadian system following circadian misalignment to preserve cardiovascular and metabolic health. © 2022 American Physiological Society. Compr Physiol 12:3621-3639, 2022.

The lungs are continually subjected to noxious and inert substances, are immunologically active, and are in a constant state of damage and repair. This makes the pulmonary system particularly vulnerable to diseases of aging. Aging can be understood as random molecular damage that is unrepaired and accumulates over time, resulting in cellular defects and tissue dysfunction. The breakdown of cellular mechanisms, including stem cell exhaustion, genomic instability, telomere attrition, epigenetic alteration, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, altered intercellular communication, and changes in the extracellular matrix is thought to advance the aging process itself. Chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and cancers illustrate a pathologic breakdown in these mechanisms beyond normal aging. The immune system becomes less effective with advancing age. There is a low-level state of chronic inflammation termed inflammaging which is thought to be driven by immunosenescence, the changes in the innate and adaptive immune systems with advancing age that lead to dysregulation and decreased effectiveness of the immune system. These processes of aging lead to expected changes in the form and function of the respiratory system, most notably a loss of lung elasticity, decrease in respiratory muscle strength, increase in ventilation-perfusion mismatching, and stiffening of the vasculature. The astute clinician is aware of these expected findings and does not often attribute dyspnea to aging alone. Maintaining a low threshold to investigate for comorbid disease and understanding how pulmonary disease presents differently in the elderly than in younger adults can improve clinical outcomes. © 2022 American Physiological Society. Compr Physiol 12:3509-3522, 2022.

Acute stroke is one of the leading causes of morbidity and mortality worldwide. Stroke-induced immune-inflammatory response occurs in the perilesion areas and the periphery. Although stroke-induced immunosuppression may alleviate brain injury, it hinders brain repair as the immune-inflammatory response plays a bidirectional role after acute stroke. Furthermore, suppression of the systemic immune-inflammatory response increases the risk of life-threatening systemic bacterial infections after acute stroke. Therefore, it is essential to explore the mechanisms that underlie the stroke-induced immune-inflammatory response. Autonomic nervous system (ANS) activation is critical for regulating the local and systemic immune-inflammatory responses and may influence the prognosis of acute stroke. We review the changes in the sympathetic and parasympathetic nervous systems and their influence on the immune-inflammatory response after stroke. Importantly, this article summarizes the mechanisms on how ANS regulates the immune-inflammatory response through neurotransmitters and their receptors in immunocytes and immune organs after stroke. To facilitate translational research, we also discuss the promising therapeutic approaches modulating the activation of the ANS or the immune-inflammatory response to promote neurologic recovery after stroke. © 2022 American Physiological Society. Compr Physiol 12:3665-3704, 2022.

Advancements in machine learning and computing methods have given new life and great excitement to one of the most essential diagnostic tools to date-the electrocardiogram (ECG). The application of artificial intelligence-enabled ECG (AI-ECG) has resulted in the ability to identify electrocardiographic signatures of conventional and unique variables and pathologies, giving way to tremendous clinical potential. However, what these AI-ECG models are detecting that the human eye is missing remains unclear. In this article, we highlight some of the recent developments in the field and their potential clinical implications, while also attempting to shed light on the physiologic and pathophysiologic features that enable these models to have such high diagnostic yield. © 2022 American Physiological Society. Compr Physiol 12:3417-3424, 2022.

The extracellular matrix (ECM) provides structural support and imparts a wide variety of environmental cues to cells. In the past decade, a growing body of work revealed that the mechanical properties of the ECM, commonly known as matrix stiffness, regulate the fundamental cellular processes of the lung. There is growing appreciation that mechanical interplays between cells and associated ECM are essential to maintain lung homeostasis. Dysregulation of ECM-derived mechanical signaling via altered mechanosensing and mechanotransduction pathways is associated with many common lung diseases. Matrix stiffening is a hallmark of lung fibrosis. The stiffened ECM is not merely a sequelae of lung fibrosis but can actively drive the progression of fibrotic lung disease. In this article, we provide a comprehensive view on the role of matrix stiffness in lung health and disease. We begin by summarizing the effects of matrix stiffness on the function and behavior of various lung cell types and on regulation of biomolecule activity and key physiological processes, including host immune response and cellular metabolism. We discuss the potential mechanisms by which cells probe matrix stiffness and convert mechanical signals to regulate gene expression. We highlight the factors that govern matrix stiffness and outline the role of matrix stiffness in lung development and the pathogenesis of pulmonary fibrosis, pulmonary hypertension, asthma, chronic obstructive pulmonary disease (COPD), and lung cancer. We envision targeting of deleterious matrix mechanical cues for treatment of fibrotic lung disease. Advances in technologies for matrix stiffness measurements and design of stiffness-tunable matrix substrates are also explored. © 2022 American Physiological Society. Compr Physiol 12:3523-3558, 2022.

Endothelial cells form the innermost layer of all blood vessels and are the only vascular component that remains throughout all vascular segments. The cerebral vasculature has several unique properties not found in the peripheral circulation; this requires that the cerebral endothelium be considered as a unique entity. Cerebral endothelial cells perform several functions vital for brain health. The cerebral vasculature is responsible for protecting the brain from external threats carried in the blood. The endothelial cells are central to this requirement as they form the basis of the blood-brain barrier. The endothelium also regulates fibrinolysis, thrombosis, platelet activation, vascular permeability, metabolism, catabolism, inflammation, and white cell trafficking. Endothelial cells regulate the changes in vascular structure caused by angiogenesis and artery remodeling. Further, the endothelium contributes to vascular tone, allowing proper perfusion of the brain which has high energy demands and no energy stores. In this article, we discuss the basic anatomy and physiology of the cerebral endothelium. Where appropriate, we discuss the detrimental effects of high blood pressure on the cerebral endothelium and the contribution of cerebrovascular disease endothelial dysfunction and dementia. © 2022 American Physiological Society. Compr Physiol 12:3449-3508, 2022.

Iron is an essential metal element whose bioavailability is tightly regulated. Under normal conditions, systemic and cellular iron homeostases are synchronized for optimal function, based on the needs of each system. During metabolic dysfunction, this synchrony is lost, and markers of systemic iron homeostasis are no longer coupled to the iron status of key metabolic organs such as the liver and adipose tissue. The effects of dysmetabolic iron overload syndrome in the liver have been tied to hepatic insulin resistance, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis. While the existence of a relationship between iron dysregulation and metabolic dysfunction has long been acknowledged, identifying correlative relationships is complicated by the prognostic reliance on systemic measures of iron homeostasis. What is lacking and perhaps more informative is an understanding of how cellular iron homeostasis changes with metabolic dysfunction. This article explores bidirectional relationships between different proteins involved in iron homeostasis and metabolic dysfunction in the liver. © 2022 American Physiological Society. Compr Physiol 12:3641-3663, 2022.

Aging is a slow process that affects all organs, and the lung is no exception. At the alveolar level, aging increases the airspace size with thicker and stiffer septal walls and straighter and thickened collagen and elastic fibers. This creates a microenvironment that interferes with the ability of cells in the parenchyma to maintain normal homeostasis and respond to injury. These changes also make the lung more susceptible to disease such as emphysema. Emphysema is characterized by slow but progressive remodeling of the deep alveolar regions that leads to airspace enlargement and increased but disorganized elastin and collagen deposition. This remodeling has been attributed to ongoing inflammation that involves inflammatory cells and the cytokines they produce. Cellular senescence, another consequence of aging, weakens the ability of cells to properly respond to injury, something that also occurs in emphysema. These factors conspire to make alveolar walls more prone to mechanical failure, which can set emphysema in motion by driving inflammation through immune stimulation by protein fragments. Both aging and emphysema are influenced by microenvironmental conditions such as local inflammation, chemical makeup, tissue stiffness, and mechanical stresses. Although aging and emphysema are not equivalent, they have the potential to influence each other in synergistic ways; aging sets up the conditions for emphysema to develop, while emphysema may accelerate cellular senescence and thus aging itself. This article focuses on the similarities and differences between the remodeled microenvironment of the aging and emphysematous lung, with special emphasis on the alveolar septal wall. © 2022 American Physiological Society. Compr Physiol 12:3559-3574, 2022.

Frailty is a complex syndrome affecting a growing sector of the global population as medical developments have advanced human mortality rates across the world. Our current understanding of frailty is derived from studies conducted in the laboratory as well as the clinic, which have generated largely phenotypic information. Far fewer studies have uncovered biological underpinnings driving the onset and progression of frailty, but the stage is set to advance the field with preclinical and clinical assessment tools, multiomics approaches together with physiological and biochemical methodologies. In this article, we provide comprehensive coverage of topics regarding frailty assessment, preclinical models, interventions, and challenges as well as clinical frameworks and prevalence. We also identify central biological mechanisms that may be at play including mitochondrial dysfunction, epigenetic alterations, and oxidative stress that in turn, affect metabolism, stress responses, and endocrine and neuromuscular systems. We review the role of metabolic syndrome, insulin resistance and visceral obesity, focusing on glucose homeostasis, adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and nicotinamide adenine dinucleotide (NAD⁺ ) as critical players influencing the age-related loss of health. We further focus on how immunometabolic dysfunction associates with oxidative stress in promoting sarcopenia, a key contributor to slowness, weakness, and fatigue. We explore the biological mechanisms involved in stem cell exhaustion that affect regeneration and may contribute to the frailty-associated decline in resilience and adaptation to stress. Together, an overview of the interplay of aging biology with genetic, lifestyle, and environmental factors that contribute to frailty, as well as potential therapeutic targets to lower risk and slow the progression of ongoing disease is covered. © 2022 American Physiological Society. Compr Physiol 12:1-46, 2022.