Inhibition of Acid-induced Lung Injury by Hyperosmolar Sucrose in Rats

Safdar, Zeenat; Yiming, Maimiti; Grünig, Gabriele; Bhattacharya, Jahar

doi:10.1164/rccm.200501-005oc

Cited by 33 publications

(24 citation statements)

References 34 publications

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“…Therefore, we investigated the influence of the CSK polymerization state on the recoil response of the tether to osmotic stress. Consistent with prior reports on hypertonically challenged neutrophils (18) and sucrose-perfused alveolar capillaries (19), exposure of A549 cells to hypertonic media was associated with the translocation of cortactin to the subcortical CSK and consequent F-actin nucleation and assembly (Fig. 3) (21).…”

Section: Osmotic Stress Alters Pm-csk Adhesive Interactionssupporting

confidence: 90%

Determinants of plasma membrane wounding by deforming stress

Oeckler¹,

Lee

Park

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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Once excess liquid gains access to air spaces of an injured lung, the act of breathing creates and destroys foam and thereby contributes to the wounding of epithelial cells by interfacial stress. Since cells are not elastic continua, but rather complex network structures composed of solid as well as liquid elements, we hypothesize that plasma membrane (PM) wounding is preceded by a phase separation, which results in blebbing. We postulate that interventions such as a hypertonic treatment increase adhesive PM-cytoskeletal (CSK) interactions, thereby preventing blebbing as well as PM wounds. We formed PM tethers in alveolar epithelial cells and fibroblasts and measured their retractive force as readout of PM-CSK adhesive interactions using optical tweezers. A 50-mOsm increase in media osmolarity consistently increased the tether retractive force in epithelial cells but lowered it in fibroblasts. The osmo-response was abolished by pretreatment with latrunculin, cytochalasin D, and calcium chelation. Epithelial cells and fibroblasts were exposed to interfacial stress in a microchannel, and the fraction of wounded cells were measured. Interventions that increased PM-CSK adhesive interactions prevented blebbing and were cytoprotective regardless of cell type. Finally, we exposed ex vivo perfused rat lungs to injurious mechanical ventilation and showed that hypertonic conditioning reduced the number of wounded subpleural alveolus resident cells to baseline levels. Our observations support the hypothesis that PM-CSK adhesive interactions are important determinants of the cellular response to deforming stress and pave the way for preclinical efficacy trials of hypertonic treatment in experimental models of acute lung injury. alveolar epithelial cell; acute lung injury; interfacial stress; osmotic response; cytoprotection THE SYNDROME OF ventilator-induced lung injury (VILI) contributes to the morbidity and mortality of critically ill patients (25). The clinical manifestations of the syndrome are indistinguishable from those of all-cause acute lung injury and at their core reflect a mechanotransduction event, i.e., the effects of deforming stress on cell and tissue injury, remodeling, and repair. The complex topographical distributions of lung mechanical properties, and hence of parenchymal stress and strain together with the numerous and nuanced injury manifestations, make it very difficult to establish mechanistic cause and effect relationships on the scale of interest, e.g., that of individual cells. Our research, therefore, focuses on a very specific mechanotransduction event, namely physical stress-related epithelial cell wounding and repair, which we believe contributes to the pathogenesis VILI.In the current study, we present a body of work in which we have explored the effects of hypertonic exposure on cell wounding in experimental models ranging from individual cells to rodent VILI preparations. The experiments were not designed to test the preclinical efficacy of an intervention, but rather to explore a cell bio...

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Section: Osmotic Stress Alters Pm-csk Adhesive Interactionssupporting

confidence: 90%

Determinants of plasma membrane wounding by deforming stress

Oeckler¹,

Lee

Park

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…We determined blood-free lung water content by the method of Selinger and colleagues (62), which we have used previously (63,64). We excised mouse lungs from anesthetized mice in the absence of treatment or 3 hours after intranasal instillation of bacteria.…”

Section: Methodsmentioning

confidence: 99%

Disruption of staphylococcal aggregation protects against lethal lung injury

Hook

Islam

Parker

et al. 2018

Journal of Clinical Investigation

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“…Using a force transducer (BG-10; Durham Instruments), we induced weight transients to quantify Kf in isolated blood-perfused mouse lungs (35,36). Briefly, the method entails establishing an isogravimetric (constant-weight) baseline.…”

Section: Kfmentioning

confidence: 99%

Connexin 43 mediates spread of Ca2+ -dependent proinflammatory responses in lung capillaries

Parthasarathi

Ichimura

Monma

et al. 2006

Journal of Clinical Investigation

144

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Acute lung injury (ALI), which is associated with a mortality of 30-40%, is attributable to inflammation that develops rapidly across the lung's vast vascular surface, involving an entire lung or even both lungs. No specific mechanism explains this extensive inflammatory spread, probably because of the lack of approaches for detecting signal conduction in lung capillaries. Here, we addressed this question by applying the photolytic uncaging approach to induce focal increases in Ca 2+ levels in targeted endothelial cells of alveolar capillaries. Uncaging caused Ca 2+ levels to increase not only in the targeted cell, but also in vascular locations up to 150 mm from the target site, indicating that Ca 2+ was conducted from the capillary to adjacent vessels. No such conduction was evident in mouse lungs lacking endothelial connexin 43 (Cx43), or in rat lungs in which we pretreated vessels with peptide inhibitors of Cx43. These findings provide the first direct evidence to our knowledge that interendothelial Ca 2+ conduction occurs in the lung capillary bed and that Cx43-containing gap junctions mediate the conduction. A proinflammatory effect was evident in that induction of increases in Ca 2+ levels in the capillary activated expression of the leukocyte adherence receptor P-selectin in venules. Further, peptide inhibitors of Cx43 completely blocked thrombin-induced microvascular permeability increases. Together, our findings reveal a novel role for Cx43-mediated gap junctions, namely as conduits for the spread of proinflammatory signals in the lung capillary bed. Gap junctional mechanisms require further consideration in the understanding of ALI.

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Inhibition of Acid-induced Lung Injury by Hyperosmolar Sucrose in Rats

Cited by 33 publications

References 34 publications

Determinants of plasma membrane wounding by deforming stress

Determinants of plasma membrane wounding by deforming stress

Disruption of staphylococcal aggregation protects against lethal lung injury

Connexin 43 mediates spread of Ca2+ -dependent proinflammatory responses in lung capillaries

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