Lung-derived soluble mediators are pathogenic in ventilator-induced lung injury
ABSTRACT Ventilator-induced lung injury (VILI) due to high tidal volume (V(T)) is associated with increased levels of circulating factors that may contribute to, or be markers of, injury. This study investigated if exclusively lung-derived circulating factors produced during high V(T) ventilation can cause or worsen VILI. In isolated perfused mouse lungs, recirculation of perfusate worsened injury (compliance impairment, microvascular permeability, edema) induced by high V(T). Perfusate collected from lungs ventilated with high V(T) and used to perfuse lungs ventilated with low V(T) caused similar compliance impairment and permeability and caused a dose-dependent decrease in transepithelial electrical resistance (TER) across rat distal lung epithelial monolayers. Circulating soluble factors derived from the isolated lung thus contributed to VILI and had deleterious effects on the lung epithelial barrier. These data demonstrate transferability of an injury initially caused exclusively by mechanical ventilation and provides novel evidence for the biotrauma hypothesis in VILI. Mediators of the TER decrease were heat-sensitive, transferable via Folch extraction, and (following ultrafiltration, 3 kDa) comprised both smaller and larger molecules. Although several classes of candidate mediators, including protein cytokines (e.g., tumor necrosis factor-α, interleukin-6, macrophage inflammation protein-1α) and lipids (e.g., eicosanoids, ceramides, sphingolipids), have been implicated in VILI, only prostanoids accumulated in the perfusate in a pattern consistent with a pathogenic role, yet cyclooxygenase inhibition did not protect against injury. Although no single class of factor appears solely responsible for the decrease in barrier function, the current data implicate lipid-soluble protein-bound molecules as not just markers but pathogenic mediators in VILI.
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ABSTRACT: Mechanical ventilation is an indispensable supportive intervention for acute respiratory failure. However, mechanical ventilation can provoke ventilator-induced lung injury, which remains one of the major causes of morbidity and mortality in critically ill patients. Excessive inflammatory response characterized by infiltration of inflammatory cells and overproduction of inflammatory mediators contributes to the pathogenesis of ventilator-induced lung injury. At present, apart from the protective ventilation strategy, no other pharmacological intervention is available to attenuate ventilator-induced lung injury. Heme oxygenase-1 (HO-1) is the inducible isoform of the first and rate-limiting enzyme which degrades heme into carbon monoxide, ferritin and bilirubin. Accumulating evidence suggests that HO-1 system may function as a crucial negative regulator in the modulation of inflammatory process. This anti-inflammatory action of HO-1 is mediated essentially by the regulation of the key cells involved in inflammation and restoration of the balance between pro-inflammatory and anti-inflammatory mediators. Therefore, HO-1 system represents a promising therapeutic target for intervention of ventilator-induced lung injury.European journal of pharmacology 12/2011; 677(1-3):1-4. DOI:10.1016/j.ejphar.2011.12.010 · 2.68 Impact Factor
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ABSTRACT: Comparisons of negative versus positive pressure ventilation have imperfectly matched the pressure-time profile or the lung volume history, or have incompletely applied in vivo negative pressure to include the complete thoracic wall and abdomen. Negative pressure exerts the same pattern of lung distension as positive pressure when the pressure-time and volume history profiles are identical and the application of negative pressure is over the whole lung. (1) In isolated (ex vivo) and (2) intact (in vivo) mouse lungs (n = 4/group) (sealed chamber enclosing either the whole lung or whole mouse except for external airway opening), identical and inverse-tidal, square-wave pressure-time profiles were obtained with positive and negative pressure ventilation. (3) Following an identical volume history, surfactant-depleted rabbits (n = 7) were randomly assigned to sustained, static equivalent positive versus negative pressures. (4) Surfactant-depleted anesthetized rabbits (n = 10) with identical volume histories were randomized to positive versus negative ventilation with identical pressure-time characteristics. Matched positive and negative pressure time profiles in ex vivo and in vivo mice resulted in identical tidal volumes. Identical (negative vs. positive) sustained static pressures resulted in similar PaO(2) and end expiratory lung volumes. Positive and negative ventilation with identical volume histories and pressure time characteristics showed no difference in oxygenation or lung volumes. Historical comparisons suggested better oxygenation with negative pressure when the volume history was not identical. These data do not support major biological differences between negative and positive pressure ventilation when waveforms and lung volume history are matched.European Journal of Intensive Care Medicine 02/2012; 38(5):879-85. DOI:10.1007/s00134-012-2512-5 · 5.54 Impact Factor