Metabolic theory of pulmonary arterial hypertension: connecting mitochondrial roles with disease control

Pulmonary arterial hypertension (PAH) is characterized by enhanced pulmonary vascular resistance, which causes right ventricular pressure overload and can lead to right-sided heart failure and death. A close link between PAH and cancer has been extensively suggested, with increasing evidence of a metabolic theory that underlies the pathogenesis of both diseases, mainly due to similarities in the processes responsible for triggering a hyperproliferative and apoptosis-resistant phenotype in both cardiopulmonary and malignant cells. Similar to cancer, abnormalities in mitochondrial biogenesis might lead to the following consequences: dysfunction of this organelle, which, in turn, causes the Warburg effect, a shift from mitochondrial respiration toward glycolysis, culminating in mitophagy in diseased pulmonary vessels and right ventricular cardiomyocytes. The role of these mitochondrial abnormalities offers new therapeutic avenues. Therefore, this study reviews the bases of mitochondrial derangements in PAH and explores the therapeutic implications of mitochondrial dysfunction and metabolic disturbances in cells from the pulmonary vasculature and right ventricular myocardium by addressing promising and challenging areas of investigation.La hipertensión arterial pulmonar (HAP) se caracteriza por una mayor resistencia vascular pulmonar, que provoca una sobrecarga de presión del ventrículo derecho (VD) y puede provocar insuficiencia cardíaca del lado derecho y la muerte. Se ha sugerido ampliamente un vínculo estrecho entre la HAP y el cáncer, con evidencia creciente de una teoría metabólica que subyace a la patogénesis de ambas enfermedades, principalmente debido a las similitudes en los procesos responsables de desencadenar un fenotipo hiperproliferativo y resistente a la apoptosis tanto en células cardiopulmonares como malignas. De manera similar al cáncer, las anomalías en la biogénesis mitocondrial pueden tener las siguientes consecuencias: Disfunción de este orgánulo, que a su vez provoca el efecto Warburg, un cambio de la respiración mitocondrial hacia la glucólisis, que culmina en una mitofagia en los vasos pulmonares enfermos y en los cardiomiocitos del ventrículo derecho. El papel de estas anomalías mitocondriales ofrece nuevas vías terapéuticas. Por lo tanto, este estudio revisa las bases de los trastornos mitocondriales en la HAP y explora las implicaciones terapéuticas de la disfunción mitocondrial y los trastornos metabólicos en las células de la vasculatura pulmonar y el miocardio del VD abordando áreas de investigación prometedoras y desafiantes.Sociedad Argentina de Fisiologí

Development of different degrees of elastase-induced emphysema in mice: a randomized controlled experimental study

Introduction: Mouse models of emphysema are important tools for testing different therapeutic strategies. The aim of this study was to develop a mouse model of emphysema induced by different doses of elastase in order to produce different degrees of severity.Methods: Thirty female mice (C57BL/6) were used in this study. Different doses of porcine pancreatic elastase were administered intratracheally once a week for four weeks, as follows: 0.1 U (n=8), 0.15 U (n=7), and 0.2 U (n=7). Control mice (n=8) received 50 microL of sterile saline solution intratracheally. Lung mechanics were analyzed by plethysmography. Mean linear intercept and volume fraction occupied by collagen and elastic fibers were determined.Results: An increase in lung resistance was observed with 0.2 U of elastase [median (P-25-P75): 2.02 (1.67; 2.34) cmH2O.s/mL], as well as a decrease in tidal volume and minute ventilation. Peak expiratory flow increased significantly in the groups treated with 0.15 U and 0.2 U of elastase. Mean linear intercept was higher with 0.15 U and 0.2 U of elastase, with destruction of alveolar walls [median (P-25-P75): 30.31 (26.65-43.13) microm and 49.49 (31.67-57.71) microm respectively]. The volume fraction occupied by collagen and elastic fibers was lower in the group receiving 0.2 U of elastase.Conclusion: Four intratracheal instillations of 0.2 U of elastase once a week induced changes in lung function and histology, producing an experimental model of severe pulmonary emphysema, whereas 0.15 U resulted in only histological changes.Introduction: Mouse models of emphysema are important tools for testing different therapeutic strategies. The aim of this study was to develop a mouse model of emphysema induced by different doses of elastase in order to produce different degrees of severity. Methods: Thirty female mice (C57BL/6) were used in this study. Different doses of porcine pancreatic elastase were administered intratracheally once a week for four weeks, as follows: 0.1 U (n=8), 0.15 U (n=7), and 0.2 U (n=7). Control mice (n=8) received 50 microL of sterile saline solution intratracheally. Lung mechanics were analyzed by plethysmography. Mean linear intercept and volume fraction occupied by collagen and elastic fibers were determined. Results: An increase in lung resistance was observed with 0.2 U of elastase [median (P-25-P75): 2.02 (1.67; 2.34) cmH2O.s/mL], as well as a decrease in tidal volume and minute ventilation. Peak expiratory flow increased significantly in the groups treated with 0.15 U and 0.2 U of elastase. Mean linear intercept was higher with 0.15 U and 0.2 U of elastase, with destruction of alveolar walls [median (P-25-P75): 30.31 (26.65-43.13) microm and 49.49 (31.67-57.71) microm respectively]. The volume fraction occupied by collagen and elastic fibers was lower in the group receiving 0.2 U of elastase. Conclusion: Four intratracheal instillations of 0.2 U of elastase once a week induced changes in lung function and histology, producing an experimental model of severe pulmonary emphysema, whereas 0.15 U resulted in only histological changes

Development of different degrees of elastaseinduced emphysema in mice : a randomized controlled experimental study

Introduction: Mouse models of emphysema are important tools for testing different therapeutic strategies. The aim of this study was to develop a mouse model of emphysema induced by different doses of elastase in order to produce different degrees of severity. Methods: Thirty female mice (C57BL/6) were used in this study. Different doses of porcine pancreatic elastase were administered intratracheally once a week for four weeks, as follows: 0.1 U (n=8), 0.15 U (n=7), and 0.2 U (n=7). Control mice (n=8) received 50 microL of sterile saline solution intratracheally. Lung mechanics were analyzed by plethysmography. Mean linear intercept and volume fraction occupied by collagen and elastic fibers were determined. Results: An increase in lung resistance was observed with 0.2 U of elastase [median (P-25-P75): 2.02 (1.67; 2.34) cmH2O.s/mL], as well as a decrease in tidal volume and minute ventilation. Peak expiratory flow increased significantly in the groups treated with 0.15 U and 0.2 U of elastase. Mean linear intercept was higher with 0.15 U and 0.2 U of elastase, with destruction of alveolar walls [median (P-25-P75): 30.31 (26.65-43.13) microm and 49.49 (31.67-57.71) microm respectively]. The volume fraction occupied by collagen and elastic fibers was lower in the group receiving 0.2 U of elastase. Conclusion: Four intratracheal instillations of 0.2 U of elastase once a week induced changes in lung function and histology, producing an experimental model of severe pulmonary emphysema, whereas 0.15 U resulted in only histological changes

Endotoxin-Induced Emphysema Exacerbation: A Novel Model of Chronic Obstructive Pulmonary Disease Exacerbations Causing Cardiopulmonary Impairment and Diaphragm Dysfunction

Chronic obstructive pulmonary disease (COPD) is a progressive disorder of the lung parenchyma which also involves extrapulmonary manifestations, such as cardiovascular impairment, diaphragm dysfunction, and frequent exacerbations. The development of animal models is important to elucidate the pathophysiology of COPD exacerbations and enable analysis of possible therapeutic approaches. We aimed to characterize a model of acute emphysema exacerbation and evaluate its consequences on the lung, heart, and diaphragm. Twenty-four Wistar rats were randomly assigned into one of two groups: control (C) or emphysema (ELA). In ELA group, animals received four intratracheal instillations of pancreatic porcine elastase (PPE) at 1-week intervals. The C group received saline under the same protocol. Five weeks after the last instillation, C and ELA animals received saline (SAL) or E. coli lipopolysaccharide (LPS) (200 μg in 200 μl) intratracheally. Twenty-four hours after saline or endotoxin administration, arterial blood gases, lung inflammation and morphometry, collagen fiber content, and lung mechanics were analyzed. Echocardiography, diaphragm ultrasonography (US), and computed tomography (CT) of the chest were done. ELA-LPS animals, compared to ELA-SAL, exhibited decreased arterial oxygenation; increases in alveolar collapse (p < 0.0001), relative neutrophil counts (p = 0.007), levels of cytokine-induced neutrophil chemoattractant-1, interleukin (IL)-1β, tumor necrosis factor-α, IL-6, and vascular endothelial growth factor in lung tissue, collagen fiber deposition in alveolar septa, airways, and pulmonary vessel walls, and dynamic lung elastance (p < 0.0001); reduced pulmonary acceleration time/ejection time ratio, (an indirect index of pulmonary arterial hypertension); decreased diaphragm thickening fraction and excursion; and areas of emphysema associated with heterogeneous alveolar opacities on chest CT. In conclusion, we developed a model of endotoxin-induced emphysema exacerbation that affected not only the lungs but also the heart and diaphragm, thus resembling several features of human disease. This model of emphysema should allow preclinical testing of novel therapies with potential for translation into clinical practice

Impact of Bacillus Calmette–Guérin Moreau vaccine on lung remodeling in experimental asthma

AbstractWe analyzed the effects of different administration routes and application times of the BCG-Moreau strain on airway and lung inflammation and remodeling in a murine model of allergic asthma. BALB/c mice (n=168) were divided into two groups. The first group received BCG-Moreau strain while the second group received saline using the same protocol. BCG or saline were intradermally or intranasally injected one or two months before the induction of asthma. Mice were further sensitized and challenged with ovalbumin or received saline. Twenty-four hours after the last challenge, BCG prevented the triggering of pro-inflammatory cytokines, probably by increasing Foxp3 and interleukin (IL)-10, modulating eosinophil infiltration and collagen fiber deposition, thus reducing airway hyperresponsiveness. In conclusion, BCG-Moreau prevented lung remodeling in the present model of allergic asthma, regardless of administration route and time of vaccination. These beneficial effects may be related to the increase in regulatory T cells and to IL-10 production in tandem with decreased Th2 cytokines (IL-4, IL-5, and IL-13)

Y-27632 is associated with corticosteroid-potentiated control of pulmonary remodeling and inflammation in guinea pigs with chronic allergic inflammation

Abstract\ud \ud Background\ud Previously, we showed that treatment with the Rho-kinase inhibitor Y-27632 was able to control airway responsiveness, inflammation, remodeling, and oxidative stress in an animal model of asthma, suggesting that this drug is beneficial in asthma. However, studies evaluating the effects of these inhibitors in conjunction with corticosteroids on chronic pulmonary inflammation have not been conducted. Therefore, we evaluated the effects of treatment with the Rho-kinase inhibitor Y-27632, with or without concurrent dexamethasone treatment, on airway and lung tissue mechanical responses, inflammation, extracellular matrix remodeling, and oxidative stress in guinea pigs with chronic allergic inflammation.\ud \ud \ud Methods\ud The guinea pigs were subjected to seven ovalbumin or saline inhalation exposures. Treatment with Y-27632 (1 mM) and dexamethasone (2 mg/kg) started at the fifth inhalation. Seventy-two hours after the seventh inhalation, the pulmonary mechanics were evaluated and exhaled nitric oxide (ENO) levels were determined. The lungs were removed and histological analysis was performed using morphometry.\ud \ud \ud Results\ud The treatment of guinea pigs with the Rho-kinase inhibitor and dexamethasone (ORC group) decreased ENO, the maximal mechanical responses after antigen challenge, inflammation, extracellular matrix remodeling and oxidative stress in the lungs.\ud This therapeutic strategy reduced the levels of collagen and IFN-γ in the airway walls, as well as IL-2, IFN-γ, 8-iso-PGF2α and NF-κB in the distal parenchyma, when compared to isolated treatment with corticosteroid or Rho-kinase inhibitor (P < 0.05) and reduced the number of TIMP-1-positive cells and eosinophils in the alveolar septa compared to corticosteroid-treated animals (P < 0.05). The combined treatment with the Rho-kinase inhibitor and the corticosteroid provided maximal control over the remodeling response and inflammation in the airways and parenchyma.\ud \ud \ud Conclusions\ud Rho-kinase inhibition, alone or in combination with corticosteroids, can be considered a future pharmacological tool for the control of asthma.We thank Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) for their financial support

Understanding the mechanisms of ventilator-induced lung injury using animal models

Abstract Mechanical ventilation is a life-saving therapy in several clinical situations, promoting gas exchange and providing rest to the respiratory muscles. However, mechanical ventilation may cause hemodynamic instability and pulmonary structural damage, which is known as ventilator-induced lung injury (VILI). The four main injury mechanisms associated with VILI are as follows: barotrauma/volutrauma caused by overstretching the lung tissues; atelectrauma, caused by repeated opening and closing of the alveoli resulting in shear stress; and biotrauma, the resulting biological response to tissue damage, which leads to lung and multi-organ failure. This narrative review elucidates the mechanisms underlying the pathogenesis, progression, and resolution of VILI and discusses the strategies that can mitigate VILI. Different static variables (peak, plateau, and driving pressures, positive end-expiratory pressure, and tidal volume) and dynamic variables (respiratory rate, airflow amplitude, and inspiratory time fraction) can contribute to VILI. Moreover, the potential for lung injury depends on tissue vulnerability, mechanical power (energy applied per unit of time), and the duration of that exposure. According to the current evidence based on models of acute respiratory distress syndrome and VILI, the following strategies are proposed to provide lung protection: keep the lungs partially collapsed (SaO2 > 88%), avoid opening and closing of collapsed alveoli, and gently ventilate aerated regions while keeping collapsed and consolidated areas at rest. Additional mechanisms, such as subject-ventilator asynchrony, cumulative power, and intensity, as well as the damaging threshold (stress–strain level at which tidal damage is initiated), are under experimental investigation and may enhance the understanding of VILI

Close down the lungs and keep them resting to minimize ventilator-induced lung injury

Abstract This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2018. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2018. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901

Controvérsias acerca da acidose hipercápnica na síndrome do desconforto respiratório agudo Controversies involving hypercapnic acidosis in acute respiratory distress syndrome

A síndrome do desconforto respiratório agudo é caracterizada por uma reação inflamatória difusa do parênquima pulmonar induzida por um insulto direto ao epitélio alveolar (síndrome do desconforto respiratório agudo pulmonar) ou indireto por meio do endotélio vascular (síndrome do desconforto respiratório agudo extrapulmonar). A principal estratégia terapêutica da síndrome do desconforto respiratório agudo é o suporte ventilatório. Entretanto, a ventilação mecânica pode agravar a lesão pulmonar. Nesse contexto, uma estratégia ventilatória protetora com baixo volume corrente foi proposta. Tal estratégia reduziu a taxa de mortalidade dos pacientes com síndrome do desconforto respiratório agudo, porém acarretou acidose hipercápnica. O presente artigo apresenta uma revisão da literatura acerca dos efeitos da acidose hipercápnica na síndrome do desconforto respiratório agudo. Para tal, realizou-se uma revisão sistemática da literatura científica conforme critérios já estabelecidos para análise documental incluindo artigos experimentais e clínicos sobre o tema, usando-se como bases de dados MedLine, LILACS, SciElo, PubMed, Cochrane. A acidose hipercápnica é defendida por alguns autores como moduladora do processo inflamatório da síndrome do desconforto respiratório agudo. Entretanto, estudos clínicos e experimentais acerca dos efeitos da acidose hipercápnica têm demonstrado resultados controversos. Logo, é fundamental a realização de mais pesquisas para elucidar o papel da acidose hipercápnica na síndrome do desconforto respiratório agudo.<br>Acute respiratory distress syndrome is characterized by a diffuse inflammatory reaction of lung parenchyma induced by a direct insult to the alveolar epithelium (pulmonary acute respiratory distress syndrome) or an indirect lesion through the vascular endothelium (extrapulmonary acute respiratory distress syndrome). The main therapeutic strategy for acute respiratory distress syndrome is the ventilatory support. However, mechanical ventilation can worsen lung injury. In this context, a protective ventilatory strategy with low tidal volume has been proposed. The use of low tidal volume reduced the mortality rate of acute respiratory distress syndrome patients, but result in hypercapnic acidosis. The current article presents a review of literature on the effects of permissive hypercapnia in acute respiratory distress syndrome. To that end, we carried out a systematic review of scientific literature based on established criteria for documental analysis including clinical and experimental articles, using as data bases MedLine, LILACS, SciELO, PubMed, Cochrane. Hypercapnic acidosis has been considered by some authors as a modulator of the inflammatory process of acute respiratory distress syndrome. However, clinical and experimental studies on the effects of hypercapnic acidosis have shown controversial results. Therefore it is important to better elucidate the role of hypercapnic acidosis in acute respiratory distress syndrome