The Evolution of Cholesterol-Rich Membrane in Oxygen Adaption: The Respiratory System as a Model.

The increase in atmospheric oxygen levels imposed significant environmental pressure on primitive organisms concerning intracellular oxygen concentration management. Evidence suggests the rise of cholesterol, a key molecule for cellular membrane organization, as a cellular strategy to restrain free oxygen diffusion under the new environmental conditions. During evolution and the increase in organismal complexity, cholesterol played a pivotal role in the establishment of novel and more complex functions associated with lipid membranes. Of these, caveolae, cholesterol-rich membrane domains, are signaling hubs that regulate important in situ functions. Evolution resulted in complex respiratory systems and molecular response mechanisms that ensure responses to critical events such as hypoxia facilitated oxygen diffusion and transport in complex organisms. Caveolae have been structurally and functionally associated with respiratory systems and oxygen diffusion control through their relationship with molecular response systems like hypoxia-inducible factors (HIF), and particularly as a membrane-localized oxygen sensor, controlling oxygen diffusion balanced with cellular physiological requirements. This review will focus on membrane adaptations that contribute to regulating oxygen in living systems

Simulations demonstrate a simple network to be sufficient to control branch point selection, smooth muscle and vasculature formation during lung branching morphogenesis

Proper lung functioning requires not only a correct structure of the conducting airway tree, but also the simultaneous development of smooth muscles and vasculature. Lung branching morphogenesis is strongly stereotyped and involves the recursive use of only three modes of branching. We have previously shown that the experimentally described interactions between Fibroblast growth factor (FGF)10, Sonic hedgehog (SHH) and Patched (Ptc) can give rise to a Turing mechanism that not only reproduces the experimentally observed wildtype branching pattern but also, in part counterintuitive, patterns in mutant mice. Here we show that, even though many proteins affect smooth muscle formation and the expression of Vegfa, an inducer of blood vessel formation, it is sufficient to add FGF9 to the FGF10/SHH/Ptc module to successfully predict simultaneously the emergence of smooth muscles in the clefts between growing lung buds, and Vegfa expression in the distal sub-epithelial mesenchyme. Our model reproduces the phenotype of both wildtype and relevant mutant mice, as well as the results of most culture conditions described in the literature.Comment: Initially published at Biology Ope

Deconvoluting lung evolution: from phenotypes to gene regulatory networks

Speakers in this symposium presented examples of respiratory regulation that broadly illustrate principles of evolution from whole organ to genes. The swim bladder and lungs of aquatic and terrestrial organisms arose independently from a common primordial “respiratory pharynx” but not from each other. Pathways of lung evolution are similar between crocodiles and birds but a low compliance of mammalian lung may have driven the development of the diaphragm to permit lung inflation during inspiration. To meet the high oxygen demands of flight, bird lungs have evolved separate gas exchange and pump components to achieve unidirectional ventilation and minimize dead space. The process of “screening” (removal of oxygen from inspired air prior to entering the terminal units) reduces effective alveolar oxygen tension and potentially explains why nonathletic large mammals possess greater pulmonary diffusing capacities than required by their oxygen consumption. The “primitive” central admixture of oxygenated and deoxygenated blood in the incompletely divided reptilian heart is actually co-regulated with other autonomic cardiopulmonary responses to provide flexible control of arterial oxygen tension independent of ventilation as well as a unique mechanism for adjusting metabolic rate. Some of the most ancient oxygen-sensing molecules, i.e., hypoxia-inducible factor-1alpha and erythropoietin, are up-regulated during mammalian lung development and growth under apparently normoxic conditions, suggesting functional evolution. Normal alveolarization requires pleiotropic growth factors acting via highly conserved cell–cell signal transduction, e.g., parathyroid hormone-related protein transducing at least partly through the Wingless/int pathway. The latter regulates morphogenesis from nematode to mammal. If there is commonality among these diverse respiratory processes, it is that all levels of organization, from molecular signaling to structure to function, co-evolve progressively, and optimize an existing gas-exchange framework

Emerging Approaches to Understanding Microvascular Endothelial Heterogeneity: A Roadmap for Developing Anti-Inflammatory Therapeutics

The endothelium is the inner layer of all blood vessels and it regulates hemostasis. It also plays an active role in the regulation of the systemic inflammatory response. Systemic inflammatory disease often results in alterations in vascular endothelium barrier function, increased permeability, excessive leukocyte trafficking, and reactive oxygen species production, leading to organ damage. Therapeutics targeting endothelium inflammation are urgently needed, but strong concerns regarding the level of phenotypic heterogeneity of microvascular endothelial cells between different organs and species have been expressed. Microvascular endothelial cell heterogeneity in different organs and organ-specific variations in endothelial cell structure and function are regulated by intrinsic signals that are differentially expressed across organs and species; a result of this is that neutrophil recruitment to discrete organs may be regulated differently. In this review, we will discuss the morphological and functional variations in differently originated microvascular endothelia and discuss how these variances affect systemic function in response to inflammation. We will review emerging in vivo and in vitro models and techniques, including microphysiological devices, proteomics, and RNA sequencing used to study the cellular and molecular heterogeneity of endothelia from different organs. A better understanding of microvascular endothelial cell heterogeneity will provide a roadmap for developing novel therapeutics to target the endothelium

Calcium dynamics and related alterations in pulmonary hypertension associated with heart failure

Congestive heart failure (CHF) represents an important Canadian health problem. Most patients with CHF develop pulmonary hypertension (PH), which is an important marker that signals progression of the disease and its poor outcome. Significant advances have been made for the treatment of heart failure (HF). Nevertheless, the morbidity and mortality among patients with advanced heart HF, who have developed PH remains high. Increased pulmonary vascular pressure (PVP) observed in PH leads to increased vascular tone and vascular remodelling associated with altered vasodilatory responses. It is noteworthy that a decrease in vasodilatory responses has been observed in PH. At the core of vasodilatory alterations lies endothelial dysfunction. This hallmark of most cardiovascular diseases is associated with alterations in calcium (Ca2+) homeostasis. Although global Ca2+ plays a role in a wide range of cellular functions, this thesis work focused on the impact of local Ca2+ signalling in endothelial cells (ECs). Among the different types of local Ca2+ signals, Ca2+ pulsars were identified. Ca2+ pulsars are local endothelial Ca2+ signals whose activity is finely regulated by physiological agents that modulate intracellular levels of inositol 1,4,5-triphosphate (IP3) and Ca2+. Ca2+ pulsars have been shown to have an effect on several important cellular functions. In mesenteric arteries, Ca2+ pulsars induce endotheliuminduced relaxation of vascular smooth muscle cells. Up until now, the regulatory mechanisms of Ca2+ pulsars remain to be uncovered. The spatio-temporal characteristics of Ca2+ pulsars suggest that they could play a role in the control of pulmonary vascular tone, potentially involving more transmembrane ion channels, as well as regulatory proteins. Transient receptor potential vanilloid 4 (TRPV4) channels are non-selective mechanosensitive osmo-regulated cation channels broadly expressed in a number of tissues. Activation of TRPV4 channels allows Ca2+ entry into the cell. A number of studies have shown the implication of TRPV4 as well as other channels from the TRP family in PH. Endothelial Ca2+-related pathophysiological mechanisms modulating pulmonary vascular tone and leading to the development of group II PH are poorly defined. In addition, the scarcity of studies exploring the pathophysiology and therapies of group II PH resides in the lack of validated small animal models with an adequate determination of the presence and severity of PH. The work in this thesis identified and characterized for the first time intracellular Ca2+ pulsars in pulmonary endothelium and their alterations in a clinically relevant mouse model of group II PH that was developed. In addition, this work revealed the implication of endothelial TRPV4 channels in Ca2+ pulsars dysregulation in group II-PH.L'insuffisance cardiaque (IC) représente un problème de santé important au Canada. La plupart des patients atteints d'IC développent une hypertension pulmonaire (HP), qui est un marqueur de la progression de la maladie et de son mauvais pronostic. Des progrès significatifs ont été réalisés pour le traitement de l'IC. Néanmoins, la morbidité et la mortalité chez les patients atteints d'IC avancée, qui ont développé l’HP reste élevée. L'augmentation de la pression vasculaire pulmonaire (PVP) observée en HP entraîne une augmentation du tonus vasculaire et un remodelage vasculaire associés à des réponses vasodilatatrices altérées. En effet, une diminution des réponses vasodilatatrices a été observée dans l'HP. La dysfonction endothéliale est au coeur des altérations vasodilatatrices. Cette caractéristique de la plupart des maladies cardiovasculaires est associée à des altérations de l'homéostasie du calcium (Ca2+). Bien que le Ca2+ global joue un rôle dans un grand nombre de fonctions cellulaires, la présente thèse est concentrée sur l'impact de la signalisation calcique locale dans les cellules endothéliales (CE). Parmi les différents types de signaux calciques locaux, les pulsars ont été identifiés. Les pulsars calciques sont des évènements endothéliaux locaux dont l'activité est finement régulée par des agents physiologiques qui modulent les niveaux intracellulaires d'inositol 1,4,5-triphosphate (IP3) et de Ca2+. Les pulsars ont un effet sur plusieurs fonctions cellulaires importantes. Dans les artères mésentériques, les pulsars induisent une relaxation des cellules musculaires lisses vasculaires. Jusqu'à présent, les mécanismes de régulation des pulsars Ca2+ restent à découvrir. Les caractéristiques spatio-temporelles des pulsars suggèrent qu'ils pourraient jouer un rôle dans le contrôle du tonus vasculaire pulmonaire, impliquant potentiellement plus de canaux ioniques transmembranaires, ainsi que des protéines régulatrices. Les canaux TRP de la famille vanilloïde 4 (TRPV4) sont des canaux cationiques méchanosensitifs, non sélectifs, largement exprimés dans un nombre de tissus. L'activation des canaux TRPV4 permet l'entrée de Ca2+ dans la cellule. Des études ont montré l'implication de TRPV4 ainsi que d'autres canaux de la famille TRP dans l’HP. Les mécanismes physiopathologiques liés au Ca2+ endothélial modulant le tonus vasculaire pulmonaire et conduisant au développement de l’HP du groupe II sont mal définis. En outre, la rareté des études explorant la physiopathologie et les thérapies de l’HP du groupe II réside dans l'absence de modèles animaux validés pour l’étude de l’HP du groupe II, avec une détermination adéquate de la présence et de la sévérité de l'HP. Les travaux issus de cette thèse ont identifié et caractérisé pour la première fois des pulsars Ca2+ intracellulaires dans l'endothélium pulmonaire et leurs altérations dans un modèle de souris cliniquement significatif de l’HP de groupe II qui a été développé. En outre, ce travail a révélé l'implication des canaux TRPV4 endothéliaux dans la dérégulation des pulsars Ca2+ dans l’HP du groupe II

The avian lingual and laryngeal apparatus within the context of the head and jaw apparatus, with comparisons to the mammalian condition: Functional morphology and biomechanics of evaporative cooling, feeding, drinking, and vocalization

© Springer International Publishing AG 2017. All rights reserved. The lingual and laryngeal apparatus are the mobile and active organs within the oral cavity, which serves as a gateway to the respiratory and alimentary systems in terrestrial vertebrates. Both organs play multiple roles in alimentation and vocalization besides respiration, but their structures and functions differ fundamentally in birds and mammals, just as the skull and jaws differ fundamentally in these two vertebrate classes. Furthermore, the movements of the lingual and laryngeal apparatus are interdependent with each other and with themovements of the jaw apparatus in complex and littleunderstood ways. Therefore, rather than updating the existing numerous reviews of the diversity in lingual morphology of birds, this chapter will concentrate on the functionalmorphological interdependences and interactions of the lingual and laryngeal apparatus with each other and with the skull and jaw apparatus. It Will

Penyediaan modul pembelajaran secara komputer (Computer aided fixed learning module-CAFLM)

FLM (Fixed Learning Module) telah dijadikan bahan untuk dimasukkan ke dalam program CAFLM (Computer aided fixed learning module) di mana isi kandungannya dipindahkan dari poster ke dalam komputer. Segala isi kandungannya masih lagi dikekalkan. Modul-modul yang berkaitan dengan fisiologi telah dipilih dan dibahagikan mengikut tajuk tertentu seperti sistem pernafasan, sistem percernaan dan sistem penglihatan. Proses menyiapkan CAFLM dilakukan dengan menaip semula teks, melukis serta mengedit gambar yang terkandung dalam poster FLM

High altitude-induced pulmonary oedema

Almost one mountain trekker or climber out of two develops several symptoms of high altitude illness after a rapid ascent (>300m/day) to an altitude above 4000m. Individual susceptibility is the most important determinant for the occurrence of high altitude pulmonary oedema (HAPE). Symptoms associated with HAPE are incapacitating fatigue, chest tightness, dyspnoea at the slightest effort, orthopnoea, and cough with due to haemoptysis in an advanced stage of the disease pink frothy sputum. The hallmark of HAPE is an excessively elevated pulmonary artery pressure (mean pressures of 35 and 55mmHg), which precedes the development of pulmonary oedema. Elevated pulmonary capillary pressure and protein- as well as red blood cell-rich oedema fluid without signs of inflammation in its early stage are characteristic findings. Furthermore, decreased fluid clearance from the alveoli may contribute to this non-cardiogenic pulmonary oedema. Immediate descent or supplemental oxygen and nifedipine are recommended until descent is possible. Susceptible individuals can prevent HAPE by slow ascent: an average gain of altitude not exceeding 400m/day above an altitude of 2500m. If progressive high altitude acclimatization is not possible, a prophylaxis with nifedipine should be recommende

INTRODUCTION TO HUMAN PHYSIOLOGY FOR MEDICAL STUDENTS

With recent advances in the fielded of human physiology, it has become urgent to provide an up to date review in the subject of human physiology.This book to help medical student in understanding modern human physiology. It presents the whole subject in brief comprehensive and up to date form.I hope this book will be a real help to undergraduate medical students, as well as to postgraduate and candidates of higher degree, in the field of human physiology

Interventional Pulmonology and Pulmonary Hypertension

This book, published by IntechOpen, focuses on interesting aspects of pulmonary medicine. The first section of the book is dedicated to interventional pulmonology, and includes updates on bronchial thermoplasty, virtual bronchoscopy, and endobronchial ultrasound. The second section highlights special aspects of pulmonary circulation and pulmonary hypertension. Throughout the book, the authors offer us not only a "vigorous" review of the current literature but also a research path to further advancement