Pressure is proinflammatory in lung venular capillaries

Kuebler, Wolfgang M.; Ying, Xiaoyou; Singh, Baljit; Issekutz, Andrew C.; Bhattacharya, Jahar

doi:10.1172/jci6872

Cited by 135 publications

(120 citation statements)

References 62 publications

(81 reference statements)

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“…It may be that sustained and increasing high pressures of sufficient duration in untreated HAPE can trigger inflammation [81], or it represents part of the healing process of a markedly disrupted alveolar-capillary barrier that occurs in the most severe cases of HAPE, especially with alveolar haemorrhage, since haem and other breakdown products of red cell haemoglobin are chemotactic for neutrophils [82]. Despite overwhelming evidence against a primary inflammatory alteration of the alveolar-capillary barrier in HAPE, it is nevertheless conceivable that any concurrent process altering the permeability of the alveolar-capillary barrier will lower the pressure required for formation of oedema.…”

Section: Inflammationmentioning

confidence: 99%

Acute high-altitude sickness

2017

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At any point 1-5 days following ascent to altitudes ⩾2500 m, individuals are at risk of developing one of three forms of acute altitude illness: acute mountain sickness, a syndrome of nonspecific symptoms including headache, lassitude, dizziness and nausea; high-altitude cerebral oedema, a potentially fatal illness characterised by ataxia, decreased consciousness and characteristic changes on magnetic resonance imaging; and high-altitude pulmonary oedema, a noncardiogenic form of pulmonary oedema resulting from excessive hypoxic pulmonary vasoconstriction which can be fatal if not recognised and treated promptly. This review provides detailed information about each of these important clinical entities. After reviewing the clinical features, epidemiology and current understanding of the pathophysiology of each disorder, we describe the current pharmacological and nonpharmacological approaches to the prevention and treatment of these diseases.

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Section: Inflammationmentioning

confidence: 99%

Acute high-altitude sickness

2017

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“…CYT as also expression of the leukocyte adhesion receptor, P-selectin, within minutes of the challenge (1). Notably, these responses localized at capillary branch points, suggesting the existence of a spatial strategy that spares a major part of the capillary surface during inflammatory initiation.…”

mentioning

confidence: 93%

“…Critical to the lung's innate immunity are endothelial cells (EC) 3 that institute rapid signaling by increasing the cytosolic Ca 2ϩ (Ca 2ϩ CYT ) (1,2). In a mechanical model of the lung's proinflammatory response in EC of lung capillaries, elevating vascular pressure increased Ca 2ϩ…”

mentioning

confidence: 99%

Mitochondrial Reactive Oxygen Species Regulate Spatial Profile of Proinflammatory Responses in Lung Venular Capillaries

Parthasarathi

Ichimura

Quadri

et al. 2002

The Journal of Immunology

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Cytokine-induced lung expression of the endothelial cell (EC) leukocyte receptor P-selectin initiates leukocyte rolling. To understand the early EC signaling that induces the expression, we conducted real-time digital imaging studies in lung venular capillaries. To compare receptor- vs nonreceptor-mediated effects, we infused capillaries with respectively, TNF-α and arachidonate. At concentrations adjusted to give equipotent increases in the cytosolic Ca2+, both agents increased reactive oxygen species (ROS) production and EC P-selectin expression. Blocking the cytosolic Ca2+ increases abolished ROS production; blocking ROS production abrogated P-selectin expression. TNF-α, but not arachidonate, released Ca2+ from endoplasmic stores and increased mitochondrial Ca2+. Furthermore, Ca2+ depletion abrogated TNF-α responses partially, but arachidonate responses completely. These differences in Ca2+ mobilization by TNF-α and arachidonate were reflected in spatial patterning in the capillary in that the TNF-α effects were localized at branch points, while the arachidonate effects were nonlocalized and extensive. Furthermore, mitochondrial blockers inhibited the TNF-α- but not the arachidonate-induced responses. These findings indicate that the different modes of Ca2+ mobilization determined the spatial patterning of the proinflammatory response in lung capillaries. Responses to TNF-α revealed that EC mitochondria regulate the proinflammatory process by generating ROS that activate P-selectin expression.

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“…To further understand this protective mechanism, we examined the functional, cellular, and molecular changes induced by I/R in the hamster cheek pouch (7,8) and by pressure elevation in isolated blood-perfused rat lung preparations (9,10) in response to treatments with ITF1697. Significant increase in microvascular perfusion and decreased vascular permeability after post-ischemic reperfusion were seen in treated animals.…”

Section: Introductionmentioning

confidence: 99%

ITF1697, a Stable Lys-Pro-Containing Peptide, Inhibits Weibel-Palade Body Exocytosis Induced by Ischemia/Reperfusion and Pressure Elevation

Bertuglia

Ichimura

Fossati

et al. 2007

Mol Med

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A number of Lys-Pro-containing short peptides have been described as possessing a variety of biological activities in vitro. Because of limited metabolic stability, however, their efficacy in vivo is uncertain. To exploit the pharmacological potential of LysPro-containing short peptides, we synthesized a series of chemically modified forms of these peptides. One of them, ITF1697 (Gly-(Nα-Et)Lys-Pro-Arg) was stable in vivo and particularly efficacious in experimental models of disseminated endotoxemia and of cardiovascular disorders. Using intravital fluorescence microscopy, we studied the peptide cellular and molecular basis of protection in the Syrian hamster cheek pouch microcirculation subjected to ischemia/reperfusion (I/R) and in pressure elevationinduced proinflammatory responses in isolated Sprague-Dawley rat lungs. Continuous intravenous infusion of ITF1697 at 0.1 to 100 μg/kg/min nearly completely protected the cheek pouch microcirculation from I/R injury as measured by decreased vascular permeability and increased capillary perfusion. Adhesion of leukocytes and platelets to blood vessels was strongly inhibited by the peptide. ITF1697 exerted its activity at the early stages of endothelial activation and inhibited P-selectin and von Willebrand factor secretion. Further mechanistic studies in the rat lung preparation revealed that the peptide inhibited the intracellular Ca 2+-dependent fusion of Weibel-Palade bodies with the plasma membrane. The ability of ITF1697 to inhibit the early functions of activated endothelial cells, such as the exocytosis of Weibel-Palade bodies, represents a novel and promising pharmacological tool in model of pathologies of a variety of microvascular disorders.

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Pressure is proinflammatory in lung venular capillaries

Cited by 135 publications

References 62 publications

Acute high-altitude sickness

Acute high-altitude sickness

Mitochondrial Reactive Oxygen Species Regulate Spatial Profile of Proinflammatory Responses in Lung Venular Capillaries

ITF1697, a Stable Lys-Pro-Containing Peptide, Inhibits Weibel-Palade Body Exocytosis Induced by Ischemia/Reperfusion and Pressure Elevation

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