Endothelial cells as early sensors of pulmonary 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: 89%

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

Wilkinson

Schittny

Reinhardt

et al. 2008

Developmental Dynamics

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“…When lungs suffer relatively mild forms of interstitial pulmonary edema, the lipid microdomains of lung cell surface membranes undergo a substantial reorganization (158,159). The functional consequence of membrane remodeling, which is almost certainly accompanied by changes in surface protein expression, remains to be explored.…”

Section: Cellular Remodeling: Prevention Of Plasma Membrane Woundingmentioning

confidence: 99%

Cellular Stress Failure in Ventilator-injured Lungs

Vlahakis

Hubmayr

2005

Am J Respir Crit Care Med

188

120

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The clinical and experimental literature has unequivocally established that mechanical ventilation with large tidal volumes is injurious to the lung. However, uncertainty about the micromechanics of injured lungs and the numerous degrees of freedom in ventilator settings leave many unanswered questions about the biophysical determinants of lung injury. In this review we focus on experimental evidence for lung cells as injury targets and the relevance of these studies for human ventilator-associated lung injury. In vitro, the stress-induced mechanical interactions between matrix and adherent cells are important for cellular remodeling as a means for preventing compromise of cell structure and ultimately cell injury or death. In vivo, these same principles apply. Large tidal volume mechanical ventilation results in physical breaks in alveolar epithelial and endothelial plasma membrane integrity and subsequent triggering of proinflammatory signaling cascades resulting in the cytokine milieu and pathologic and physiologic findings of ventilatorassociated lung injury. Importantly, though, alveolar cells possess cellular repair and remodeling mechanisms that in addition to protecting the stressed cell provide potential molecular targets for the prevention and treatment of ventilator-associated lung injury in the future.

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“…Although lung overexpansion exacerbates lung injury in mechanically ventilated patients (1), our aim was to avoid excessive hyperinflation that might elicit independent signaling effects secondary to events such as pulmonary edema (23) and stress fracture (24). Previous reports indicate that stretch-mediated increase of vascular diameter by ‫ف‬ 8% induces Ca 2ϩ and NO signaling in lung endothelial cells in situ (25,26).…”

Section: Discussionmentioning

confidence: 99%

Sequence of Endothelial Signaling during Lung Expansion

Yiming

Parthasarathi²,

Issekutz³

et al. 2005

Am J Respir Cell Mol Biol

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Although high tidal volume ventilation exacerbates lung injury, the mechanisms underlying the inflammatory response are not clear. Here, we exposed isolated lungs to high or low tidal volume ventilation, while perfusing lungs with whole blood, or blood depleted of leukocytes and platelets. Then, we determined signaling responses in freshly isolated lung endothelial cells by means of immunoblotting and immunofluorescence approaches. In depleted blood perfusion, high tidal volume induced modest increases in both P-selectin expression on the endothelial surface, and in endothelial protein tyrosine phosphorylation. Both high tidal volume-induced responses were markedly enhanced in the presence of whole blood perfusion. However, a P-selectin-blocking antibody given together with whole blood perfusion inhibited the responses down to levels corresponding to those for depleted blood perfusion. These findings indicate that the full proinflammatory response occurs in two stages. First, lung distension causes modest endothelial activation. Second, subsequent endothelial-inflammatory cell interactions augment P-selectin expression and tyrosine phosphorylation. We conclude that interactions of circulating inflammatory cells with P-selectin critically determine proinflammatory endothelial activation during high tidal volume ventilation.Keywords: leukocytes; lung; mechanical; P-selectin; phosphorylation Although mechanical ventilators provide essential respiratory support in lung injury, a potential difficulty is that the high tidal volumes delivered by mechanical ventilation may independently exacerbate lung injury (1). Since high tidal volume (HV) causes excessive expansion of pulmonary alveoli, and since stretching cultured endothelial cells activates kinases (2), it is proposed that alveolar overexpansion stretches endothelial cells, causing inflammatory responses. However, no direct data in situ support this view.Because endothelial cells are critical for initiating lung inflammation, it is important to understand the endothelial signaling sequence activated by HV ventilation. An important but unanswered question is whether lung expansion is the predominant factor that induces proinflammatory endothelial signaling, or whether secondary inputs are required. The stretch hypothesis is derived largely from findings in cultured cells (2). Hence, the possibility exists that even under HV conditions, lung endothelial cells in situ may not stretch sufficiently to account entirely for the induced inflammatory consequences.To test this hypothesis, we exposed lungs to HV ventilation. Our aim was to determine the extent to which alveolar stretch, (Received in original form April 11, 2005 and in final form July 19, 2005) This study was supported by grant HL54157 to S.B. from the National Institutes of Health.Correspondence and requests for reprints should be addressed to Sunita Bhattacharya, M.D., St. Luke's-Roosevelt Hospital Center, AJA #510, 1000 10th Avenue, New York, NY 10019. E-mail: sb80@columbia.edu as opposed to inflammato...

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Endothelial cells as early sensors of pulmonary interstitial edema

Cited by 49 publications

References 28 publications

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

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

Cellular Stress Failure in Ventilator-injured Lungs

Sequence of Endothelial Signaling during Lung Expansion

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