RESUMEN
The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 infection is a serious global concern. Increased morbidity and mortality is associated with older age, male gender, cardiovascular disease, diabetes, and smoking. As COVID-19 spreads from coastal borders, both state to state and country to country, our understanding of its pathophysiology has evolved. Age and type 2 diabetes mellitus (T2DM) play especially important roles in COVID-19 progression. T2DM is an age-related disease associated with metabolic syndrome, obesity, insulin resistance (hyperinsulinemia), hyperlipidemia, hypertension, hyperglycemia, and endothelial activation and dysfunction. This review evaluates the relationships and intersection between endothelial cell activation and dysfunction in T2DM and COVID-19. COVID-19 induces multiple injuries of the terminal bronchioles and alveolar blood-gas barrier and associated ultrastructural tissue remodeling. COVID-19 may unmask multiple vulnerabilities associated with T2DM including damage to the endothelial glycocalyx and multiple end-organ macro and microvascular diseases. Unmasking existing vulnerabilities in diabetic patients with COVID-19 is important. Globally, we must come together to better understand why T2DM is associated with increased COVID-19 morbidity and mortality.
Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/fisiopatología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/fisiopatología , Células Endoteliales/fisiología , Síndrome Metabólico/complicaciones , Síndrome Metabólico/fisiopatología , Neumonía Viral/complicaciones , Neumonía Viral/fisiopatología , Animales , Barrera Alveolocapilar/patología , Barrera Alveolocapilar/fisiopatología , Bronquiolos/patología , Bronquiolos/fisiopatología , COVID-19 , Comorbilidad , Infecciones por Coronavirus/epidemiología , Diabetes Mellitus Tipo 2/epidemiología , Reposicionamiento de Medicamentos , Células Endoteliales/patología , Humanos , Síndrome Metabólico/epidemiología , Modelos Biológicos , Pandemias , Neumonía Viral/epidemiología , Alveolos Pulmonares/fisiología , Alveolos Pulmonares/fisiopatología , Ratas , SARS-CoV-2 , Cicatrización de Heridas/fisiologíaRESUMEN
PURPOSE OF REVIEW: Epithelial barrier defects are being appreciated in various inflammatory disorders; however, causal underlying mechanisms are lacking. In this review, we describe the disruption of the airway epithelium with regard to upper and lower airway diseases, the role of epigenetic alterations underlying this process, and potential novel ways of interfering with dysfunctional epithelial barriers as a novel therapeutic approach. RECENT FINDINGS: A defective epithelial barrier, impaired innate defence mechanisms or hampered epithelial cell renewal are found in upper and lower airway diseases. Barrier dysfunction might facilitate the entrance of foreign substances, initiating and facilitating the onset of disease. Latest data provided novel insights for possible involvement of epigenetic alterations induced by inflammation or other unknown mechanisms as a potential mechanism responsible for epithelial defects. Additionally, these mechanisms might precede disease development, and represent a novel therapeutic approach for restoring epithelial defects. SUMMARY: A better understanding of the role of epigenetics in driving and maintaining epithelial defects in various inflammatory diseases, using state-of-the-art biology tools will be crucial in designing novel therapies to protect or reconstitute a defective airway epithelial barrier.
Asunto(s)
Barrera Alveolocapilar , Mucosa Respiratoria , Enfermedades Respiratorias , Barrera Alveolocapilar/fisiología , Barrera Alveolocapilar/fisiopatología , Epigénesis Genética , Humanos , Inflamación , Mucosa Respiratoria/fisiología , Mucosa Respiratoria/fisiopatología , Enfermedades Respiratorias/genética , Enfermedades Respiratorias/inmunologíaRESUMEN
Oxygen diffusion across the air-blood barrier in the lung is commensurate with metabolic needs and ideally allows full equilibration between alveolar and blood partial oxygen pressures. We estimated the alveolo-capillary O2 equilibration in 18 healthy subjects at sea level at rest and after exposure to increased O2 demand, including work at sea level and on hypobaric hypoxia exposure at 3840 m (PA ~ 50 mmHg). For each subject we estimated O2 diffusion capacity (DO2), pulmonary capillary blood volume (Vc) and cardiac output ([Formula: see text]). We derived blood capillary transit time [Formula: see text] and the time constant of the equilibration process ([Formula: see text], ß being the slope of the hemoglobin dissociation curve). O2 equilibration at the arterial end of the pulmonary capillary was defined as [Formula: see text]. Leq greately differed among subjects in the most demanding O2 condition (work in hypoxia): lack of full equilibration was found to range from 5 to 42% of the alveolo-capillary PO2 gradient at the venous end. The present analysis proves to be sensible enough to highlight inter-individual differences in alveolo-capillary equilibration among healthy subjects.
Asunto(s)
Barrera Alveolocapilar/fisiopatología , Ejercicio Físico , Hipoxia/fisiopatología , Consumo de Oxígeno , Oxígeno/sangre , Capacidad de Difusión Pulmonar , Adulto , Gasto Cardíaco , Femenino , Voluntarios Sanos , Humanos , Masculino , Ventilación PulmonarRESUMEN
Influenza viruses are a threat to global public health resulting in ~500,000 deaths each year. Despite an intensive vaccination program, influenza infections remain a recurrent, yet unsolved public health problem. Secondary bacterial infections frequently complicate influenza infections during seasonal outbreaks and pandemics, resulting in increased morbidity and mortality. Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), is frequently associated with these co-infections, including the 2009 influenza pandemic. Damage to alveolar epithelium is a major contributor to severe influenza-bacterial co-infections and can result in gas exchange abnormalities, fluid leakage, and respiratory insufficiency. These deleterious manifestations likely involve both pathogen- and host-mediated mechanisms. However, there is a paucity of information regarding the mechanisms (pathogen- and/or host-mediated) underlying influenza-bacterial co-infection pathogenesis. To address this, we characterized the contributions of viral-, bacterial-, and host-mediated factors to the altered structure and function of alveolar epithelial cells during co-infection with a focus on the 2009 pandemic influenza (pdm2009) and MRSA. Here, we characterized pdm2009 and MRSA replication kinetics, temporal host kinome responses, modulation of MRSA virulence factors, and disruption of alveolar barrier integrity in response to pdm2009-MRSA co-infection. Our results suggest that alveolar barrier disruption during co-infection is mediated primarily through host response dysregulation, resulting in loss of alveolar barrier integrity.
Asunto(s)
Células Epiteliales Alveolares/microbiología , Células Epiteliales Alveolares/virología , Barrera Alveolocapilar/fisiopatología , Gripe Humana/fisiopatología , Infecciones Estafilocócicas/fisiopatología , Células A549 , Coinfección/microbiología , Coinfección/virología , Humanos , Subtipo H1N1 del Virus de la Influenza A , Gripe Humana/microbiología , Pulmón/patología , Staphylococcus aureus Resistente a Meticilina , Análisis por Matrices de Proteínas , Infecciones Estafilocócicas/virología , Factores de Virulencia , Replicación ViralAsunto(s)
Barrera Alveolocapilar/metabolismo , Lesión Pulmonar/metabolismo , Proteostasis , Síndrome de Dificultad Respiratoria/metabolismo , Respuesta de Proteína Desplegada , Animales , Barrera Alveolocapilar/patología , Barrera Alveolocapilar/fisiopatología , Humanos , Lesión Pulmonar/patología , Lesión Pulmonar/fisiopatología , Lesión Pulmonar/terapia , Síndrome de Dificultad Respiratoria/patología , Síndrome de Dificultad Respiratoria/fisiopatología , Síndrome de Dificultad Respiratoria/terapiaRESUMEN
The O2 diffusion limitation across the air blood barrier (DO2 and subcomponents Dm and Vc) was evaluated in 17 healthy participants exposed to hypobaric hypoxia (HA, 3840m, PIO2 â¼90mmHg). A 10% decrease in alveolar volume (VA) in all participants suggested the development of sub-clinical interstitial lung edema. In >80% of participants DO2/VA increased, reflecting an individual strategy to cope with the hypoxia stimulus by remodulating Vc or Dm. Opposite changes in Dm/Vc ratio were observed and participants decreasing Vc showed reduced alveolar blood capillary transit time. The interplay between diffusion and perfusion (cardiac output) was estimated in order to investigate the individual adaptive response to hypoxia. It appears remarkable that despite individual differences in the adaptive response to HA, diffusion limitation did not exceed â¼11% of the alveolar-venous PO2 gradient, revealing an admirable functional design of the air-blood barrier to defend the O2 diffusion/perfusion function when facing hypobaric hypoxia corresponding to 50mmHg decreased PAO2.
Asunto(s)
Barrera Alveolocapilar/fisiopatología , Hipoxia/patología , Oxígeno/sangre , Adulto , Ecocardiografía , Femenino , Humanos , Hipoxia/terapia , Masculino , Persona de Mediana Edad , Presión Parcial , Capacidad de Difusión Pulmonar/métodos , Ventilación PulmonarAsunto(s)
Capilares/patología , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/fisiopatología , Alveolos Pulmonares/patología , Barrera Alveolocapilar/fisiopatología , Capilares/fisiopatología , Dióxido de Carbono , Humanos , Hipertensión Pulmonar/clasificación , Hipertensión Pulmonar/etiología , Alveolos Pulmonares/fisiopatología , Capacidad de Difusión Pulmonar , Factores de Riesgo , SíndromeRESUMEN
Acute respiratory distress syndrome (ARDS) is a rapidly progressive hypoxemic respiratory insufficiency induced by alveolar filling mainly caused by alveolocapillary wall disruption, following direct or indirect pulmonary injury. Much less frequent in children than in adults, pediatric intensivists had long applied adult guidelines to their daily practice. In 2015, experts from the Pediatric Acute Lung Injury Consensus Conference (PALICC) published the first international guidelines specifically dedicated to pediatric ARDS. After a short summary of the history of the ARDS definition since its first report in 1967, we describe the main diagnostic and therapeutic guidelines for PALICC.
Asunto(s)
Síndrome de Dificultad Respiratoria/diagnóstico , Síndrome de Dificultad Respiratoria/terapia , Terminología como Asunto , Adolescente , Adulto , Barrera Alveolocapilar/fisiopatología , Niño , Preescolar , Diagnóstico Diferencial , Humanos , Lactante , Recién Nacido , Pronóstico , Síndrome de Dificultad Respiratoria/mortalidad , Síndrome de Dificultad Respiratoria/fisiopatología , Sociedades Médicas , Tasa de Supervivencia , Adulto JovenRESUMEN
DLCO measured in hypoxia must be corrected due to the higher affinity (increase in coefficient θ) of CO with Hb. We propose an adjustment accounting for individual changes in the equation relating DLCO to subcomponents Dm (membrane diffusive capacity) and Vc (lung capillary volume): 1/DLCO=1/Dm+1/θVc. We adjusted the individual DLCO measured in hypoxia (HA, 3269m) by interpolating the 1/DLCO to the sea level (SL) 1/θ value. Nineteen healthy subjects were studied at SL and HA. Based on the proposed adjustment, DLCO increased in HA in 53% of subjects, reflecting the increase in Dm that largely overruled the decrease in Vc. We hypothesize that a decrease in Vc (buffering microvascular filtration) and the increase in Dm (possibly resulting from a decrease in thickness of the air-blood barrier) represent the anti-edemagenic adaptation of the lung to hypoxia exposure. The efficiency of this adaptation varied among subjects as DLCO did not change in 31% of subjects and decreased in 16%.
Asunto(s)
Barrera Alveolocapilar/fisiopatología , Hipoxia/patología , Hipoxia/fisiopatología , Capacidad de Difusión Pulmonar/fisiología , Adulto , Análisis de los Gases de la Sangre , Volumen Sanguíneo/fisiología , Monóxido de Carbono/metabolismo , Femenino , Voluntarios Sanos , Hemoglobinas/metabolismo , Humanos , Masculino , Pruebas de Función Respiratoria , Estadística como AsuntoRESUMEN
A computational model of a morphologically-based alveolar capillary unit (ACU) in the rabbit is developed to relate lung fluid balance to mechanical forces between capillary surface and interstitium during development of interstitial edema. We hypothesize that positive values of interstitial liquid pressure Pliq impact on capillary transmural pressure and on blood flow. ACU blood flow, capillary recruitment and filtration are computed by modulating vascular and interstitial pressures. Model results are compared with experimental data of Pliq increasing from ~-10 (control) up to ~4cmH2O in two conditions, hypoxia and collagenase injection. For hypoxia exposure, fitting data requires a linear increase in hydraulic conductivity Lp and capillary pressure PC, that fulfils the need of increase in oxygen delivery. For severe fragmentation of capillary endothelial barrier (collagenase injection), fitting requires a rapid increase in both hydraulic and protein permeability, causing ACU de-recruitment, followed by an increase in PC as a late response to restore blood flow. In conclusion, the model allows to describe the lung adaptive response to edemagenic perturbations; the increase in Pliq, related to the low interstitial compliance, provides an efficient control of extravascular water, by limiting microvascular filtration.
Asunto(s)
Algoritmos , Barrera Alveolocapilar/metabolismo , Capilares/metabolismo , Pulmón/irrigación sanguínea , Modelos Cardiovasculares , Agua/metabolismo , Animales , Barrera Alveolocapilar/fisiopatología , Capilares/fisiopatología , Permeabilidad Capilar , Biología Computacional/métodos , Simulación por Computador , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Hipoxia/fisiopatología , Pulmón/fisiopatología , Perfusión , Presión , Edema Pulmonar/metabolismo , Edema Pulmonar/fisiopatología , Conejos , Reproducibilidad de los ResultadosAsunto(s)
Asma/historia , Investigación Biomédica/historia , Biología Celular/historia , Pulmón , Respiración , Animales , Asma/patología , Asma/fisiopatología , Fenómenos Biomecánicos , Investigación Biomédica/tendencias , Barrera Alveolocapilar/patología , Barrera Alveolocapilar/fisiopatología , Selección de Profesión , Biología Celular/tendencias , Movimiento Celular , Predicción , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Pulmón/patología , Pulmón/fisiopatologíaRESUMEN
Cardiac dysfunction of both systolic and diastolic origins leads to increased left atrial pressure, lung capillary injury and increased resistance to gas transfer. Acutely, pressure-induced trauma disrupts the endothelial and alveolar anatomical configuration and definitively causes an impairment of cellular pathways involved in fluid-flux regulation and gas exchange efficiency, a process well identified as stress failure of the alveolar-capillary membrane. In chronic heart failure (HF), additional stimuli other than pressure may trigger the true remodeling process of capillaries and small arteries characterized by endothelial dysfunction, proliferation of myofibroblasts, fibrosis and extracellular matrix deposition. In parallel there is a loss of alveolar gas diffusion properties due to the increased path from air to blood (thickening of extracellular matrix) and loss of fine molecular mechanism involved in fluid reabsorption and clearance. Deleterious changes in gas transfer not only reflect the underlying lung tissue damage but also portend independent prognostic information and may play a role in the pathogenesis of exercise limitation and ventilatory abnormalities observed in these patients. Few currently approved treatments for chronic HF have the potential to positively affect structural remodeling of the lung capillary network; angiotensin-converting enzyme inhibitors are one of the few currently established options. Recently, more attention has been paid to novel therapies specifically targeting the nitric oxide pathway as a suitable target to improve endothelial function and permeability as well as alveolar gas exchange properties.
Asunto(s)
Barrera Alveolocapilar/fisiopatología , Capilares/fisiopatología , Endotelio Vascular/fisiopatología , Insuficiencia Cardíaca/complicaciones , Enfermedades Pulmonares/etiología , Pulmón/irrigación sanguínea , Remodelación Vascular , Animales , Barrera Alveolocapilar/patología , Capilares/patología , Permeabilidad Capilar , Endotelio Vascular/patología , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/terapia , Humanos , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/fisiopatología , Enfermedades Pulmonares/diagnóstico , Enfermedades Pulmonares/fisiopatología , Enfermedades Pulmonares/terapia , Pronóstico , Intercambio Gaseoso Pulmonar , Factores de RiesgoRESUMEN
Viral pneumonia is a major cause of acute respiratory distress syndrome (ARDS). Anti-inflammatory therapies for viral-induced lung injury show promise in preclinical models. Mesenchymal stem/stromal cells (MSCs) are multipotent, self-renewing cells that secrete anti-inflammatory cytokines and epithelial and endothelial growth factors. We inoculated mice intranasally with influenza A (murine-adapted Puerto Rico/8/34) or PBS, and the mice were killed at multiple time points after infection for measures of lung injury and viral load. We report that influenza induces marked, long-lasting dysfunction of the alveolar-capillary barrier peaking at 1 wk but lasting longer than 3 wk postinfection. Weight loss, commonly employed as a criterion for euthanasia (and hence "survival"), was found to be poorly predictive of the severity of lung injury at its peak; rather, persistent weight loss 11 days postinfection identified mice with impaired injury resolution. Murine and human bone marrow-derived MSCs (obtained from the National Institutes of Health repository) were then administered intravenously during the rapid phase of injury progression. Murine MSCs (mMSCs) given two times 24 h apart failed to improve weight loss, lung water, bronchoalveolar lavage inflammation, or histology. However, mMSCs prevented influenza-induced thrombocytosis and caused a modest reduction in lung viral load at day 7. Human MSCs administered intravenously showed a similar lack of efficacy. The results demonstrate that the influenza murine model bears important similarities to the slow resolution of ARDS in patients. Despite their potent therapeutic effects in many models of acute inflammation and lung injury, MSCs do not improve influenza-mediated lung injury in mice.
Asunto(s)
Lesión Pulmonar Aguda/etiología , Barrera Alveolocapilar/fisiopatología , Capilares/fisiopatología , Gripe Humana/complicaciones , Trasplante de Células Madre Mesenquimatosas/efectos adversos , Infecciones por Orthomyxoviridae/complicaciones , Alveolos Pulmonares/fisiopatología , Lesión Pulmonar Aguda/patología , Animales , Lavado Broncoalveolar , Permeabilidad Capilar , Tratamiento Basado en Trasplante de Células y Tejidos/efectos adversos , Células Cultivadas , Femenino , Humanos , Gripe Humana/patología , Gripe Humana/terapia , Gripe Humana/virología , Células Madre Mesenquimatosas/citología , Ratones , Ratones Endogámicos C57BL , Infecciones por Orthomyxoviridae/patología , Infecciones por Orthomyxoviridae/terapia , Infecciones por Orthomyxoviridae/virologíaRESUMEN
In this review we summarize recent major advances in our understanding on the molecular mechanisms, mediators, and biomarkers of acute lung injury (ALI) and alveolar-capillary barrier dysfunction, highlighting the role of immune cells, inflammatory and noninflammatory signaling events, mechanical noxae, and the affected cellular and molecular entities and functions. Furthermore, we address novel aspects of resolution and repair of ALI, as well as putative candidates for treatment of ALI, including pharmacological and cellular therapeutic means.
Asunto(s)
Lesión Pulmonar Aguda/fisiopatología , Barrera Alveolocapilar/fisiopatología , Capilares/fisiopatología , Permeabilidad Capilar , Alveolos Pulmonares/fisiopatología , Animales , Comunicación Celular , HumanosRESUMEN
Severe malaria can trigger acute lung injury characterized by pulmonary edema resulting from increased endothelial permeability. However, the mechanism through which lung fluid conductance is altered during malaria remains unclear. To define the role that the scavenger receptor CD36 may play in mediating this response, C57BL/6J (WT) and CD36-/- mice were infected with P. berghei ANKA and monitored for changes in pulmonary endothelial barrier function employing an isolated perfused lung system. WT lungs demonstrated a >10-fold increase in two measures of paracellular fluid conductance and a decrease in the albumin reflection coefficient (σalb) compared to control lungs indicating a loss of barrier function. In contrast, malaria-infected CD36-/- mice had near normal fluid conductance but a similar reduction in σalb. In WT mice, lung sequestered iRBCs demonstrated production of reactive oxygen species (ROS). To determine whether knockout of CD36 could protect against ROS-induced endothelial barrier dysfunction, mouse lung microvascular endothelial monolayers (MLMVEC) from WT and CD36-/- mice were exposed to H2O2. Unlike WT monolayers, which showed dose-dependent decreases in transendothelial electrical resistance (TER) from H2O2 indicating loss of barrier function, CD36-/- MLMVEC demonstrated dose-dependent increases in TER. The differences between responses in WT and CD36-/- endothelial cells correlated with important differences in the intracellular compartmentalization of the CD36-associated Fyn kinase. Malaria infection increased total lung Fyn levels in CD36-/- lungs compared to WT, but this increase was due to elevated production of the inactive form of Fyn further suggesting a dysregulation of Fyn-mediated signaling. The importance of Fyn in CD36-dependent endothelial signaling was confirmed using in vitro Fyn knockdown as well as Fyn-/- mice, which were also protected from H2O2- and malaria-induced lung endothelial leak, respectively. Our results demonstrate that CD36 and Fyn kinase are critical mediators of the increased lung endothelial fluid conductance caused by malaria infection.
Asunto(s)
Células Epiteliales Alveolares/metabolismo , Barrera Alveolocapilar/metabolismo , Antígenos CD36/metabolismo , Malaria/metabolismo , Plasmodium berghei , Proteínas Proto-Oncogénicas c-fyn/metabolismo , Células Epiteliales Alveolares/patología , Animales , Barrera Alveolocapilar/fisiopatología , Antígenos CD36/genética , Eritrocitos/metabolismo , Eritrocitos/parasitología , Técnicas de Silenciamiento del Gen , Pulmón/metabolismo , Pulmón/patología , Malaria/patología , Ratones , Ratones Noqueados , Permeabilidad , Especies Reactivas de Oxígeno/metabolismo , Transducción de SeñalRESUMEN
AIM: The effects of physical exercise on oxidative stress parameters and immunocontent of NF-кß/p65 in lung of rats submitted to lung injury, as well as its possible protective effect on the changes in the alveolar-capillary barrier (total cell count, lactate dehydrogenase and total protein) in the bronchoalveolar lavage fluid (BALF) and the inflammatory infiltration in the pulmonary parenchyma were evaluated. MAIN METHODS: Wistar rats were submitted to two months of physical exercise and after this period, lung injury was induced by intratracheal instillation of lipopolysaccharide (dose of 100 µg/100 g body weight). Twelve hours after injury, the animals were sacrificed and lung and BALF were collected. KEY FINDINGS: Results showed an increase in reactive species production, lipid peroxidation, oxidative damage to protein, as well as in nitrite levels and NF-кß/p65 immunocontent in lung of rats submitted to lung injury. Physical exercise was able to totally prevent the increase in reactive species, nitrite levels and NF-кß/p65 immunocontent, but partially prevented the damage to protein. Superoxide dismutase and catalase were not changed in lung injury group, but the activities of these enzymes were increased in lung injury plus exercise group. Non-enzymatic antioxidant capacity, glutathione content and glutathione peroxidase were decreased and exercise totally prevented such effects. Rats subjected to lung injury presented an increase in total cell, lactate dehydrogenase and total protein; exercise partially prevented the increase in lactate dehydrogenase. SIGNIFICANCE: These findings suggest that physical exercise may prevent, at least partially, the oxidative damage caused by experimental lung injury, suggesting that exercise may have an important role as protector in this condition.
Asunto(s)
Barrera Alveolocapilar/metabolismo , Lesión Pulmonar/metabolismo , Estrés Oxidativo , Condicionamiento Físico Animal , Animales , Barrera Alveolocapilar/patología , Barrera Alveolocapilar/fisiopatología , Líquido del Lavado Bronquioalveolar , Catalasa/metabolismo , L-Lactato Deshidrogenasa/metabolismo , Lipopolisacáridos/toxicidad , Lesión Pulmonar/inducido químicamente , Lesión Pulmonar/patología , Lesión Pulmonar/fisiopatología , Masculino , Ratas , Ratas Wistar , Superóxido Dismutasa/metabolismo , Factor de Transcripción ReIA/metabolismoRESUMEN
In 1953 Frank Low published the first high-resolution electron micrographs of the human pulmonary blood-gas barrier. These showed that a structure only 0.3-µm thick separated the capillary blood from the alveolar gas, immediately suggesting that the barrier might be vulnerable to mechanical failure if the capillary pressure increased. However, it was 38 years before stress failure was recognized. Initially it was implicated in the pathogenesis of High Altitude Pulmonary Edema, but it was soon clear that stress failure of pulmonary capillaries is common. The vulnerability of the blood-gas barrier is a key factor in the evolution of the pulmonary circulation. As evolution progressed from the ancestors of fishes to amphibians, reptiles, and finally birds and mammals, two factors challenged the integrity of the barrier. One was the requirement for the barrier to become increasingly thin because of the greater oxygen consumption. The other was the high pulmonary capillary pressures that were inevitable before there was complete separation of the pulmonary and systemic circulations.
Asunto(s)
Evolución Biológica , Barrera Alveolocapilar/fisiopatología , Capilares/fisiología , Arteria Pulmonar/fisiología , Circulación Pulmonar/fisiología , Intercambio Gaseoso Pulmonar/fisiología , Animales , HumanosRESUMEN
Acute lung injury (ALI) is a severe illness with excess mortality and no specific therapy. Protective actions were recently uncovered for docosahexaenoic acid-derived mediators, including D-series resolvins. Here, we used a murine self-limited model of hydrochloric acid-induced ALI to determine the effects of aspirin-triggered resolvin D1 (AT-RvD1; 7S,8R,17R-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid) on mucosal injury. RvD1 and its receptor ALX/FPR2 were identified in murine lung after ALI. AT-RvD1 (~0.5-5 µg kg(-1)) decreased peak inflammation, including bronchoalveolar lavage fluid (BALF) neutrophils by ~75%. Animals treated with AT-RvD1 had improved epithelial and endothelial barrier integrity and decreased airway resistance concomitant with increased BALF epinephrine levels. AT-RvD1 inhibited neutrophil-platelet heterotypic interactions by downregulating both P-selectin and its ligand CD24. AT-RvD1 also significantly decreased levels of BALF pro-inflammatory cytokines, including interleukin (IL)-1ß, IL-6, Kupffer cells, and tumor necrosis factor-α, and decreased nuclear factor-κB-phosphorylated p65 nuclear translocation. Taken together, these findings indicate that AT-RvD1 displays potent mucosal protection and promotes catabasis after ALI.
Asunto(s)
Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Antiinflamatorios no Esteroideos/farmacología , Aspirina/farmacología , Ácidos Docosahexaenoicos/metabolismo , Inflamación/metabolismo , Mucosa Respiratoria/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Resistencia de las Vías Respiratorias , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Aspirina/administración & dosificación , Plaquetas/metabolismo , Barrera Alveolocapilar/fisiopatología , Modelos Animales de Enfermedad , Ácidos Docosahexaenoicos/biosíntesis , Epinefrina/metabolismo , Inflamación/inmunología , Mediadores de Inflamación/metabolismo , Leucocitos/inmunología , Macrófagos Alveolares/metabolismo , Masculino , Ratones , Neutrófilos/inmunología , Edema Pulmonar/inmunología , Edema Pulmonar/metabolismo , Edema Pulmonar/patología , Receptores de Formil Péptido/metabolismo , Mucosa Respiratoria/patología , Factor de Transcripción ReIA/metabolismoRESUMEN
The endothelial glycocalyx (GLX) is pivotal to vascular barrier function. We investigated the consequences of GLX degradation on pulmonary microvascular perfusion and, prompted by evidence that hydroxyethyl starch (HES) improves microcirculation, studied the effects of two HES preparations during GLX diminution. C57 BL/6 black mice lungs were explanted and perfused with 1-mL/min buffer solution containing autologous erythrocytes (red blood cells) at a hematocrit of 5%. Microvessel perfusion was quantified by video fluorescence microscopy at 0 and 90 min. To register interstitial edema, alveolar septal width was quantified. Pulmonary artery pressure (PAP), airway pressure, and left atrial pressure were recorded continuously. Lungs were randomly assigned to four groups (each n = 5): (i) control: no treatment, (ii) HEP1: heparinase I (1 mU/mL) was injected for GLX degradation, (iii) HES 130, and (iv) HES 200: one third of perfusion fluid was exchanged for 6% HES 130/0.4 or 10% HES 200/0.5 before GLX degradation. Analysis of variance on ranks and pairwise multiple comparisons were used for statistics, P < 0.05. Compared with control, GLX degradation effected perfusion failure in microvessels, increased PAP, and facilitated interstitial edema formation after a 90-min period of perfusion. In contrast to HES 200/0.5, pretreatment with HES 130/0.4 attenuated all of these consequences. Sequelae of GLX degradation in lung include perfusion failure in microvessels, interstitial edema formation, and increase in PAP. We assume that these effects are a consequence of vascular barrier dysfunction. Beneficial effects of HES 130/0.4 are presumably a result of its lower red blood cell bridging capacity compared with HES 200/0.5.
Asunto(s)
Glicocálix/metabolismo , Derivados de Hidroxietil Almidón/farmacología , Pulmón/irrigación sanguínea , Pulmón/metabolismo , Microcirculación/efectos de los fármacos , Perfusión , Sustitutos del Plasma/farmacología , Animales , Barrera Alveolocapilar/metabolismo , Barrera Alveolocapilar/patología , Barrera Alveolocapilar/fisiopatología , Humanos , Pulmón/patología , Pulmón/fisiopatología , Masculino , Ratones , Edema Pulmonar/inducido químicamente , Edema Pulmonar/metabolismo , Edema Pulmonar/fisiopatologíaRESUMEN
Chronic obstructive pulmonary disease (COPD) is characterized by a persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. From a pathological point of view, COPD is characterized by two distinct and frequently coexisting aspects: small airway abnormalities and parenchymal destruction (or emphysema). When pathological changes are localized in lung parenchyma, they will contribute to airflow limitation by reducing the elastic recoil of the lung through parenchymal destruction, as well as by reducing the elastic load applied to the airways through destruction of alveolar attachments. Conversely, when pathological changes involve the small airways, they will contribute to airflow limitation by narrowing and obliterating the lumen and by actively constricting the airways, therefore increasing the resistance. In this article we will review the structural abnormalities in small airways and their relationship with the disordered pulmonary function in COPD, in the attempt to disentangle the mechanisms contributing to the development and progression of airflow limitation in smokers. We will start by describing the normal structure of the small airways, and then observe the main pathological alterations that accumulate in this site and how they parallel pulmonary function derangement.