The lymphatic system develops and functions in parallel with the blood circulatory system (termed the "hemovasculature") and accomplishes transport of interstitial fluids, dietary lipids, and reverse transport of cholesterol, immune cells, and antigens-providing a critical homeostatic fluid balance and transmission of immune cells and mediators back to the cardiovascular system. Although the daily flow of lymph (normally 1-2 L/day under unstressed conditions) is far lower than that of daily blood flow (which is 7,500 L/day), without the adequate functioning of the lymphatics, virtually all organs and tissues would acutely suffer many different physical and inflammatory stresses ranging from edema to organ system failure. Although blood and lymphatic vessels often form in anatomic parallels to one another, our knowledge of the workings of the lymphatic system, the fine structure of lymphatic networks, how they function in different organs, and how they are regulated physiologically and immunologically are far from parallel; our knowledge of the lymphatic system still remains at only a tiny fraction of what is understood about the cardiovascular system. Although both the cardiovascular and lymphatic systems are important transport systems, what they transport and how they transport and propel these very different cargoes could not be more dissimilar. This book provides an overview of the history of the discovery (and re-discovery) of the components of the lymphatic system, lymphatic anatomy, physiological functions of lymphatics, molecular features of the lymphatic system, and clinical perspectives involving lymphatics which may be of interest to scientists, clinicians, patients, and the lay public. We provide a current understanding of some of the more important structural similarities and differences between lymphatics and the blood vascular system, their coordinated control by angiogenic and hemangiogenic growth factors and other modulators, the fate and lineage determinants which control lymphatic development, and the roles that lymphatics may play in several different diseases.

Exercise is the act of increasing metabolic rate for the purpose of enhancing physical fitness. Exercise can be one of the most stressful physiological responses that the body undertakes. With exercise, there are increases in metabolic rate, heart rate, blood flow (hyperemia), respiration, and heat production. The increased metabolic requirement during exercise is well met by an increased blood flow (functional hyperemia) and oxygen supply to the exercising tissue, which is regulated by multiple local and systemic mechanisms. The local mechanisms (factors) are responsible for mediating the muscle homeostasis and vascular conductance to match the increased metabolic requirement, whereas the systemic mechanisms are responsible for the maintenance of blood pressure and global cardiovascular homeostasis, including the increase in and redistribution of cardiac output, which is mainly mediated by sympathetic activation. For instance, the substantial decreases in vascular resistance and resultant large increase in blood flow during exercise require higher blood pressure and more cardiac output, such that the metabolically active muscle can be perfused with adequate blood flow. This book will provide an overview of the cardiovascular responses to exercise under physiological conditions as well as some pathological circumstances.

The kidney is innervated with efferent sympathetic nerve fibers reaching the renal vasculature, the tubules, the juxtaglomerular granular cells, and the renal pelvic wall. The renal sensory nerves are mainly found in the renal pelvic wall. Increases in efferent renal sympathetic nerve activity reduce renal blood flow and urinary sodium excretion by activation of 1-adrenoceptors and increase renin secretion rate by activation of 1-adrenoceptors. In response to normal physiological stimulation, changes in efferent renal sympathetic nerve activity contribute importantly to homeostatic regulation of sodium and water balance. The renal mechanosensory nerves are activated by stretch of the renal pelvic tissue produced by increases in renal pelvic tissue of a magnitude that may occur during increased urine flow rate. Under normal conditions, the renal mechanosensory nerves activated by stretch of the sensory nerves elicits an inhibitory renorenal reflex response consisting of decreases in efferent renal sympathetic nerve activity leading to natriuresis. Increasing efferent sympathetic nerve activity increases afferent renal nerve activity which, in turn, decreases efferent renal sympathetic nerve activity by activation of the renorenal reflexes. Thus, activation of the afferent renal nerves buffers changes in efferent renal sympathetic nerve activity in the overall goal of maintaining sodium balance. In pathological conditions of sodium retention, impairment of the inhibitory renorenal reflexes contributes to an inappropriately increased efferent renal sympathetic nerve activity in the presence of sodium retention. In states of renal disease or injury, there is a shift from inhibitory to excitatory reflexes originating in the kidney. Studies in essential hypertensive patients have shown that renal denervation results in long-term reduction in arterial pressure, suggesting an important role for the efferent and afferent renal nerves in hypertension.

This collaboration of two physiologists and a gastroenterologist provides medical and graduate students, medical and surgical residents, and subspecialty fellows a comprehensive summary of digestive system physiology and addresses the pathophysiological processes that underlie some GI diseases. The textual approach proceeds by organ instead of the traditional organization followed by other GI textbooks. This approach lets the reader track the food bolus as it courses through the GI tract, learning on the way each organ's physiologic functions as the bolus directly or indirectly contacts it. The book is divided into three parts: (1) Chapters 1-3 include coverage of basic concepts that pertain to all (or most) organs of the digestive system, salivation, chewing, swallowing, and esophageal function, (2) Chapters 4-6 are focused on the major secretory organs (stomach, pancreas, liver) that assist in the assimilation of a meal, and (3) Chapters 7 and 8 address the motor, transport, and digestive functions of the small and large intestines. Each chapter includes its own pathophysiology and clinical correlation section that underscores the importance of the organ's normal function.

Food and water are necessary for survival, but can only be obtained via ingestive behavior (feeding, drinking, and moving). Survival thus depends on the ability of the brain to coordinate the need for water and energy with appropriate behaviors to modify their intake as necessary for homeostasis. However, the balance of these behaviors also inherently determines body weight, and imbalances contribute to the development of weight disorders, such as obesity and anorexia nervosa. The lateral hypothalamic area (LHA) of the brain is anatomically positioned to coordinate the sensation of osmotic and energy status with goal-directed ingestive behaviors necessary to maintain homeostasis and body weight, and, hence, may hold insight into the potential treatment for energy balance disorders. This volume reviews the essential role of the LHA for the control of body weight, from its historical description as a ""feeding center"" to the current view of this LHA as a cellularly heterogeneous hub that regulates multiple aspects of physiology to influence body weight. Furthermore, we evaluate how specific LHA populations coordinate certain metabolic cues and behaviors, which may guide the development of pathway-specific interventions to improve the treatment of energy balance disorders.

Pulmonary hypertension is a life-threatening disease with no known cure. Here we provide a concise yet comprehensive review of the current knowledge about the pathophysiology of pulmonary hypertension (PH). The underlying signaling mechanisms involved in pulmonary vascular remodeling and the exaggerated vascular contractility, two characteristic features of pulmonary hypertension, are discussed in depth. The roles of inflammation, immunity, and right ventricular function in the pathobiology of pulmonary hypertension are discussed. The epidemiology of the five groups of pulmonary hypertension (World Health Organization classification; Nice, 2013) is also briefly described. A clear understanding of our current knowledge about the pathogenesis of PH is essential for further exploration of the underlying mechanisms involved in this disease and for the development of new therapeutic modalities. This book should be of interest to researchers and graduate students, both in basic research and in clinical settings, in the fields of pulmonary vascular biology and pulmonary hypertension.

Pulmonary hypertension is a life-threatening disease with no known cure. Here we provide a concise yet comprehensive review of the current knowledge about the pathophysiology of pulmonary hypertension (PH). The underlying signaling mechanisms involved in pulmonary vascular remodeling and the exaggerated vascular contractility, two characteristic features of pulmonary hypertension, are discussed in depth. The roles of inflammation, immunity, and right ventricular function in the pathobiology of pulmonary hypertension are discussed. The epidemiology of the five groups of pulmonary hypertension (World Health Organization classification; Nice, 2013) is also briefly described. A clear understanding of our current knowledge about the pathogenesis of PH is essential for further exploration of the underlying mechanisms involved in this disease and for the development of new therapeutic modalities. This book should be of interest to researchers and graduate students, both in basic research and in clinical settings, in the fields of pulmonary vascular biology and pulmonary hypertension.

Food and water are necessary for survival, but can only be obtained via ingestive behavior (feeding, drinking, and moving). Survival thus depends on the ability of the brain to coordinate the need for water and energy with appropriate behaviors to modify their intake as necessary for homeostasis. However, the balance of these behaviors also inherently determines body weight, and imbalances contribute to the development of weight disorders, such as obesity and anorexia nervosa. The lateral hypothalamic area (LHA) of the brain is anatomically positioned to coordinate the sensation of osmotic and energy status with goal-directed ingestive behaviors necessary to maintain homeostasis and body weight, and, hence, may hold insight into the potential treatment for energy balance disorders. This volume reviews the essential role of the LHA for the control of body weight, from its historical description as a ""feeding center"" to the current view of this LHA as a cellularly heterogeneous hub that regulates multiple aspects of physiology to influence body weight. Furthermore, we evaluate how specific LHA populations coordinate certain metabolic cues and behaviors, which may guide the development of pathway-specific interventions to improve the treatment of energy balance disorders.

Environmental heat stress is associated with a marked decrease in orthostatic tolerance (OT), which is defined as the ability to stand or sit upright without symptoms of dizziness, lightheadedness, presyncope, or fainting. In most healthy humans, the autonomic nervous system makes rapid and balanced adjustments to heart rate and peripheral blood flow, such that most people are able to stand up "successfully" most of the time, in most environments. The goal of this book is to discuss various aspects of the sympathetic neural response to heat stress, how the sympathetic nervous system coordinates the successful integrative physiological response to orthostasis, and what happens when it encounters both challenges simultaneously. We include overviews of mechanisms of thermoregulation and blood pressure regulation in humans, with particular focus on control of cardiac output and neurovascular control mechanisms during heat stress. We discuss the implications that these changes have for distribution of peripheral blood flow and, in particular, for blood flow to the cerebral circulation. The added stressor of dehydration is also discussed, as it so often goes hand in hand with heat stress. We end with a brief presentation of countermeasures against the decreases in OT with heat stress.

Environmental heat stress is associated with a marked decrease in orthostatic tolerance (OT), which is defined as the ability to stand or sit upright without symptoms of dizziness, lightheadedness, presyncope, or fainting. In most healthy humans, the autonomic nervous system makes rapid and balanced adjustments to heart rate and peripheral blood flow, such that most people are able to stand up ""successfully"" most of the time, in most environments. The goal of this book is to discuss various aspects of the sympathetic neural response to heat stress, how the sympathetic nervous system coordinates the successful integrative physiological response to orthostasis, and what happens when it encounters both challenges simultaneously. We include overviews of mechanisms of thermoregulation and blood pressure regulation in humans, with particular focus on control of cardiac output and neurovascular control mechanisms during heat stress. We discuss the implications that these changes have for distribution of peripheral blood flow and, in particular, for blood flow to the cerebral circulation. The added stressor of dehydration is also discussed, as it so often goes hand in hand with heat stress. We end with a brief presentation of countermeasures against the decreases in OT with heat stress.

This collaboration of two physiologists and a gastroenterologist provides medical and graduate students, medical and surgical residents, and subspecialty fellows a comprehensive summary of digestive system physiology and addresses the pathophysiological processes that underlie some GI diseases. The textual approach proceeds by organ instead of the traditional organization followed by other GI textbooks. This approach lets the reader track the food bolus as it courses through the GI tract, learning on the way each organ's physiologic functions as the bolus directly or indirectly contacts it. The book is divided into three parts: (1) Chapters 1-3 include coverage of basic concepts that pertain to all (or most) organs of the digestive system, salivation, chewing, swallowing, and esophageal function, (2) Chapters 4-6 are focused on the major secretory organs (stomach, pancreas, liver) that assist in the assimilation of a meal, and (3) Chapters 7 and 8 address the motor, transport, and digestive functions of the small and large intestines. Each chapter includes its own pathophysiology and clinical correlation section that underscores the importance of the organ's normal function.

The kidney is innervated with efferent sympathetic nerve fibers reaching the renal vasculature, the tubules, the juxtaglomerular granular cells, and the renal pelvic wall. The renal sensory nerves are mainly found in the renal pelvic wall. Increases in efferent renal sympathetic nerve activity reduce renal blood flow and urinary sodium excretion by activation of 1-adrenoceptors and increase renin secretion rate by activation of 1-adrenoceptors. In response to normal physiological stimulation, changes in efferent renal sympathetic nerve activity contribute importantly to homeostatic regulation of sodium and water balance. The renal mechanosensory nerves are activated by stretch of the renal pelvic tissue produced by increases in renal pelvic tissue of a magnitude that may occur during increased urine flow rate. Under normal conditions, the renal mechanosensory nerves activated by stretch of the sensory nerves elicits an inhibitory renorenal reflex response consisting of decreases in efferent renal sympathetic nerve activity leading to natriuresis. Increasing efferent sympathetic nerve activity increases afferent renal nerve activity which, in turn, decreases efferent renal sympathetic nerve activity by activation of the renorenal reflexes. Thus, activation of the afferent renal nerves buffers changes in efferent renal sympathetic nerve activity in the overall goal of maintaining sodium balance. In pathological conditions of sodium retention, impairment of the inhibitory renorenal reflexes contributes to an inappropriately increased efferent renal sympathetic nerve activity in the presence of sodium retention. In states of renal disease or injury, there is a shift from inhibitory to excitatory reflexes originating in the kidney. Studies in essential hypertensive patients have shown that renal denervation results in long-term reduction in arterial pressure, suggesting an important role for the efferent and afferent renal nerves in hypertension.

The lymphatic system develops and functions in parallel with the blood circulatory system (termed the "hemovasculature") and accomplishes transport of interstitial fluids, dietary lipids, and reverse transport of cholesterol, immune cells, and antigens-providing a critical homeostatic fluid balance and transmission of immune cells and mediators back to the cardiovascular system. Although the daily flow of lymph (normally 1-2 L/day under unstressed conditions) is far lower than that of daily blood flow (which is 7,500 L/day), without the adequate functioning of the lymphatics, virtually all organs and tissues would acutely suffer many different physical and inflammatory stresses ranging from edema to organ system failure. Although blood and lymphatic vessels often form in anatomic parallels to one another, our knowledge of the workings of the lymphatic system, the fine structure of lymphatic networks, how they function in different organs, and how they are regulated physiologically and immunologically are far from parallel; our knowledge of the lymphatic system still remains at only a tiny fraction of what is understood about the cardiovascular system. Although both the cardiovascular and lymphatic systems are important transport systems, what they transport and how they transport and propel these very different cargoes could not be more dissimilar. This book provides an overview of the history of the discovery (and re-discovery) of the components of the lymphatic system, lymphatic anatomy, physiological functions of lymphatics, molecular features of the lymphatic system, and clinical perspectives involving lymphatics which may be of interest to scientists, clinicians, patients, and the lay public. We provide a current understanding of some of the more important structural similarities and differences between lymphatics and the blood vascular system, their coordinated control by angiogenic and hemangiogenic growth factors and other modulators, the fate and lineage determinants which control lymphatic development, and the roles that lymphatics may play in several different diseases.

This book focuses on the structural, biochemical, and diverse functional properties of the endothelial luminal membrane glycocalyx (ELMG), an organelle which constitutes the endothelial cell "membrane." It is intended to provide the newcomer with a broad, basic, and brief perspective of the luminal endothelial vascular membrane, and for the more established investigator, a basic overview and integrated perspective of the "universe" we explore. The endothelium is an assortment of heterogeneous regulatory cells whose cytoplasm and cell membranes are joined, forming functional units. There is a tremendous amount of literature on the endothelial cell, constituting seemingly isolated and distinct fields of encapsulated research. However, the multifunctional properties of some molecules give rise to an overlap of findings, frequently ignored between the different fields. The book is divided into three parts. The first part concentrates on the structure of the ELMG, with emphasis on morphological and biochemical composition. The importance of the chemical composition to the physiological functions of the ELMG, such as sieving properties, pharmacology, and flow sensing, is the focus of the second part of the book. Finally, some of the pathologies associated with ELMG dysfunction are explored in the last section. The aim is to provide basic and well-established knowledge in the various individual fields, identify the current concepts in each area, and discuss their respective strengths and weaknesses (including hidden problems). Finally, the overall goal is to integrate areas where overlap is clearly indicated, bringing them all together to provide the first ever basic, integrative, panoramic bird's-eye view of the field.

This book reviews important aspects of polycystic kidney diseases, the latest scientific understanding of the diseases and syndromes, along with the therapies being developed. Cystic kidney diseases comprise a spectrum of genetic syndromes defined by renal cyst formation and expansion with variable extrarenal manifestations. The most prevalent disorder is the autosomal dominant polycystic kidney disease (ADPKD). It is the most common monogenetic disorder in humans and accounts for 4.4% of end-stage renal disease (ESRD) cases in the U.S. Patients inevitably progress to ESRD and require renal replacement therapy in the form of dialysis or transplantation. Through advancements in genomics and proteomics approaches, novel genes responsible for cystic diseases have been identified, further expanding our understanding of basic mechanisms of disease pathogenesis. The hallmark among all cystic genetic syndromes is the formation and growth of fluid-filled cysts, which originate from tubular epithelia of nephron segments. Cysts are the disease, and treatment strategies are being developed to target prevention or delay of cyst formation and expansion at an early stage, however no such therapy is currently approved.

This book reviews important aspects of polycystic kidney diseases, the latest scientific understanding of the diseases and syndromes, along with the therapies being developed. Cystic kidney diseases comprise a spectrum of genetic syndromes defined by renal cyst formation and expansion with variable extrarenal manifestations. The most prevalent disorder is the autosomal dominant polycystic kidney disease (ADPKD). It is the most common monogenetic disorder in humans and accounts for 4.4% of end-stage renal disease (ESRD) cases in the U.S. Patients inevitably progress to ESRD and require renal replacement therapy in the form of dialysis or transplantation. Through advancements in genomics and proteomics approaches, novel genes responsible for cystic diseases have been identified, further expanding our understanding of basic mechanisms of disease pathogenesis. The hallmark among all cystic genetic syndromes is the formation and growth of fluid-filled cysts, which originate from tubular epithelia of nephron segments. Cysts are the disease, and treatment strategies are being developed to target prevention or delay of cyst formation and expansion at an early stage, however no such therapy is currently approved.

The liver is a vital organ involved in numerous metabolic processes such as cholesterol and bile acid metabolism, biliary lipid secretion, and bile formation. Cholesterol balance across the liver has a crucial effect on influencing plasma total and LDL cholesterol levels and biliary cholesterol concentrations. Cholesterol and bile acid biosyntheses are primarily modulated by negative feedback regulatory mechanisms through the sterol regulatory element-binding protein isoform 2 (SREBP-2) and the farnesoid X receptor (FXR) pathways, respectively. The conversion of cholesterol to bile acids in the liver can balance the fecal excretion of bile acids, which is an important route for the removal of cholesterol from the body. Bile formation begins in the bile canaliculi, and maintenance of the enterohepatic circulation of bile acids results in a continuous secretion of bile. Hepatic secretion of biliary lipids is determined mainly by a group of ATP-binding cassette (ABC) transporters that are located on the canalicular membrane of hepatocytes, which are regulated by various nuclear receptors. Bile acids promote bile flow by their osmotic effects. Also, they are essential for the intestinal absorption of cholesterol, fatty acids, and fat-soluble vitamins and play an important role in aiding the digestion of dietary fat. Bile acids function as signaling molecules and anti-inflammatory agents to regulate lipid, glucose, and energy metabolism by rapidly activating nuclear receptors and cell signaling pathways. This eBook summarizes the progress in the molecular and cellular mechanisms of cholesterol and bile acid metabolism and the physical-chemistry of biliary lipids, with emphasis on biliary lipid metabolism that is regulated by nuclear receptors in the hepatobiliary system.

The mammalian gastrointestinal mucosa is a rapidly self-renewing tissue in the body, and its homeostasis is preserved through the strict regulation of epithelial cell proliferation, growth arrest, and apoptosis. The control of the growth of gastrointestinal mucosa is unique and, compared with most other tissue in the body, complex. Mucosal growth is regulated by the same hormones that alter metabolism in other tissues, but the gastrointestinal mucosa also responds to host events triggered by the ingestion and presence of food within the digestive tract. These gut hormones and peptides regulate the growth of the exocrine pancreas, gallbladder epithelium, and the mucosa of the oxyntic gland region of the stomach and the small and large intestines. Luminal factors, including nutrients or other dietary factors, secretions, and microbes that occur within the lumen and distribute over a proximal-to-distal gradient, are also crucial for maintenance of normal gut mucosal regeneration and could explain the villous-height-crypt-depth gradient and variety of adaptation, since these factors are diluted, absorbed, and destroyed as they pass down the digestive tract. Recently, intestinal stem cells, cellular polyamines, and noncoding RNAs are shown to play an important role in the regulation of gastrointestinal mucosal growth under physiological and various pathological conditions. In this book, we highlight key issues and factors that control gastrointestinal mucosal growth and homeostasis, with special emphasis on the mechanisms through which epithelial renewal and apoptosis are regulated at the cellular and molecular levels.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Variability in pathogenesis and complex pathophysiology often delay diagnosis and create significant challenges for clinical studies in this group of critically ill patients. Mainly for those reasons, there is no therapy approved so far to overcome the underlying immune dysregulation. This book provides an overview about the state of the art of sepsis diagnostics and potential future therapies. Chapter 1 focuses on the immunologic staging of sepsis-the key for successful treatment of the dysregulated hot response. Chapter 2 reveals similarities in the immune response in sepsis and cancer-opening new avenues for novel therapies. Chapter 3 introduces an important modulator of the immune response-the endogenous cannabinoid system and elucidates its role in organ dysfunction in sepsis. Facing the increasing bacterial resistance to classical antibiotics, Chapter 4 discusses two unique mechanisms to treat infection and inflammation in sepsis: iron chelation, and the sphingosine pathway. The authors, all experts in experimental and clinical sepsis research, seek to provide further understanding of the complexities of the immune response as the physiological basis for the development of new therapeutics in sepsis.

This book focuses on the structural, biochemical, and diverse functional properties of the endothelial luminal membrane glycocalyx (ELMG), an organelle which constitutes the endothelial cell "membrane." It is intended to provide the newcomer with a broad, basic, and brief perspective of the luminal endothelial vascular membrane, and for the more established investigator, a basic overview and integrated perspective of the "universe" we explore. The endothelium is an assortment of heterogeneous regulatory cells whose cytoplasm and cell membranes are joined, forming functional units. There is a tremendous amount of literature on the endothelial cell, constituting seemingly isolated and distinct fields of encapsulated research. However, the multifunctional properties of some molecules give rise to an overlap of findings, frequently ignored between the different fields. The book is divided into three parts. The first part concentrates on the structure of the ELMG, with emphasis on morphological and biochemical composition. The importance of the chemical composition to the physiological functions of the ELMG, such as sieving properties, pharmacology, and flow sensing, is the focus of the second part of the book. Finally, some of the pathologies associated with ELMG dysfunction are explored in the last section. The aim is to provide basic and well-established knowledge in the various individual fields, identify the current concepts in each area, and discuss their respective strengths and weaknesses (including hidden problems). Finally, the overall goal is to integrate areas where overlap is clearly indicated, bringing them all together to provide the first ever basic, integrative, panoramic bird's-eye view of the field.

The blood-brain barrier (BBB) is a complex and dynamic structure that protects the brain from cells within the vasculature, from the immune system and from pathogens. This barrier is present in arterioles, capillaries and venules and is formed at the level of adjacent endothelial cells, which are coupled to astrocytes, microglia, neurons and pericytes. The structure of this endothelial barrier is unique among endothelia of other organ systems and is composed of complexes made up of tight, gap and adherens junctions. In addition, it is the responsibility of the surrounding cellular elements to maintain the integrity of the junctional complexes and restrict the entry of substances from the blood into the brain. Changes in permeability of the BBB during physiologic and pathophysiologic conditions involve alterations in specific transporters at the level of the endothelium, activation of specific cellular second messenger pathways and/or the dissolution of the junctional complexes composing the BBB. This book focuses on various aspects that account for the formation and maintenance of the BBB, and on disease states that compromise this barrier.

The placenta is an organ that connects the developing fetus to the uterine wall, thereby allowing nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. Proper vascular development in the placenta is fundamental to ensuring a healthy fetus and successful pregnancy. This book provides an up-to-date summary and synthesis of knowledge regarding placental vascular biology and discusses the relevance of this vascular bed to the functions of the human placenta.