Morpho-functional analysis of lung tissue in mild  interstitial edema

Alveoli are formed in the lung by the insertion of secondary tissue folds, termed septa, which are subsequently remodeled to form the mature alveolar wall. Secondary septation requires interplay between three cell types: endothelial cells forming capillaries, contractile interstitial myofibroblasts, and epithelial cells. Here, we report that postnatal lung alveolization critically requires ephrinB2, a ligand for Eph receptor tyrosine kinases expressed by the microvasculature. Mice homozygous for the hypomorphic knockin allele ephrinB2 ⌬V/⌬V , encoding mutant ephrinB2 with a disrupted C-terminal PDZ interaction motif, show severe postnatal lung defects including an almost complete absence of lung alveoli and abnormal and disorganized elastic matrix. Lung alveolar formation is not sensitive to loss of ephrinB2 cytoplasmic tyrosine phosphorylation sites. Postnatal day 1 mutant lungs show extracellular matrix alterations without differences in proportions of major distal cell populations. We conclude that lung alveolar formation relies on endothelial ephrinB2 function. Developmental Dynamics 237:2220 -2234, 2008.

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“…5B,D,G). No signs of interstitial edema (Conforti et al, 2002;Daffara et al, 2004) or inflammatory infiltration were detected.…”

Section: Ultrastructural Findingsmentioning

confidence: 88%

Role for ephrinB2 in postnatal lung alveolar development and elastic matrix integrity

Wilkinson

Schittny

Reinhardt

et al. 2008

Developmental Dynamics

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“…A cascade of hormonal and cytotoxic activation is involved in the remodeling process that unequivocally leads to abnormalities in gas exchange (Figure 1 Tsukimoto et al 10 studied the sequential disruption of the capillary endothelial and alveolar epithelial layers during a stepwise increase in hydrostatic pressure, reproducing the transition from interstitial leakage of protein (low permeability stage) to alveolar lumen leakage of protein and erythrocytes (highpermeability stage of pulmonary edema). A number of animal studies that have focused on the biological features of alveolar stress failure have shown that mechanisms other than mechanical injury may contribute to capillary stress 11,12 . Induction of volume overload through 0.5 ml/min…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

“…11 Development of hydraulic edema leads to activation of metalloproteinases, which degrades matrix proteo glycanstherevy altering the composition of the plasma membrane and contributing to increased endothelial membrane fluidity. The weakened tensile strength of the membrane potentiates endothelial stress failure 12 .…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

Endothelial Dysfunction and Lung Capillary Injury in Cardiovascular Diseases

Guazzi¹,

Phillips²,

Arena³

et al. 2015

Progress in Cardiovascular Diseases

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Cardiac dysfunction of both systolic and diastolic origin 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 alveolarcapillary 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 limitations 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.

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“…The lung's air-blood barrier is 0.2-0.3 microns thin with a "minimum" volume of water reflecting a functionally "dry" condition that ensures a high efficiency of the gas diffusion [27]. Furthermore similarly to the pleural fluid, also lung interstitial fluid is kept at a subatmospheric pressure (also ~ -10 cmH2O) due to the powerful draining action of lymphatics in face of a very low microvascular permeability [26].…”

Section: The Pathogenesis Of Extra Vascular Lung Water (Evlw) and Pulmentioning

confidence: 99%