Sphingosine 1-Phosphate Reduces Vascular Leak in Murine and Canine Models of Acute Lung Injury

Excessive mechanical stres is a lock opener component of ventilator-associated lung injury, resulting in vivid vascular leak and an intense inflammatory replication To extend our in vitro observations concerning the barrier-protective imports of the lipid growth factor sphingosine 1-phosphate (Sph 1-P) we assessed the ability of Sph 1-P to interrupt regional pulmonary edema accumulation in clinically relevant gnawing and canine models of acute lung injury induced from combined intrabronchial endotoxin administration and high tidal tome mechanical ventilation. Intravenously delivered Sph 1-P significantly attenuated the two alveolar and vascular barrier dysfunction while significantly reducing switch formation associated with lung injury. Whole lung comput tomographic image analysis demonstrated the capability of Sph 1-P to abrogate significantly the accumulation of extravascular lung water evok according to 6-hour exposure to endotoxin. Axial density profiles and vertical density gradients localized the Sph 1-P reply to transitional zones between aerated and consolidated lung regions. Together, these consequence s indicate that Sph 1-P give an account ofs a novel therapeutic intervention for the prevention of pulmonary edema related to inflammatory injury and increased vascular permeability.

Keywords: acute lung injury; comput tomography imaging; endothelial permeability; mechanical ventilation

The solution pathophysiologic feature of acute lung injury (ALI) and ventilator-associated lung injury is a sustained duration of high-permeability lung edema, which in addition to producing physiologic derangement (hypoxemia and reduc lung compliance) increases the ne for and duration of ventilatory support. It is now appreciated that increased requirements for mechanical ventilation enhance the risk of malnutrition, nosocomial infection, and multiple organ dysfunction syndrome Clearly, therapies aimed at minimizing the vascular leak underlying ALI will decrease the duration of mechanical ventilation and may have substantial impact in succession morbidity and mortality associated with ALL Effective adjunctive therapies to treat or stop ALI or ventilator-associated lung injury, however, remain elusive (1-5)

Platelets have extended been demonstrated to enhance the integrity of the microcirculation (67) with thrombocytopenia increasing capillary permeability and accelerating fluid and protein extravasation (8 9) Infusion of platelets or platelet-released produces reverses the barrier compromise seen in thrombocytopenia (10) lately we identified sphingosine 1-phosphate (Sph 1-P) a biologically active lipid generated from hydrolysis of membrane lipids primarily in activated platelets, as the major barrierprotective outcome of platelets (11, 12). within ligation of cell surface endothelial differentiation gene receptors, Sph 1-P initiates downstream cytoskeletal reorganization, resulting in improved endothelial barrier function in vitro (12) We lately translated these in vitro observations into an in vivo archetype of sepsis/ALI in which C57BL/6 mice expos to intratracheal lipopolysaccharide (LPS) (2 mg/kg) followed through intravenous Sph 1-P (1 ?µM) demonstrated reduc lung wet-weight to dry-weight ratios, decreased extravasation of Evans azure dye into the pulmonary interstitium, and attenuated accumulation of alveolar protein after 6 and 24 hours compared with mice expos to intratracheal LP alone (13) Although gnawer models provide an efficient means to establish the therapeutic potential of barrier-protective approaches, they do not allow for evaluation of regional differences in lung mechanical and cellular behavior now well recognized as characteristic of ALI in humans (1415) Therefore, large animal experiments in injury examples with appropriate scale and mechanical characteristics are essential to the translation of these therapies into the practice of critical care medicine. As vascular barrier-protective strategies for the treatment of ALI are not commonly available, we hypothesized that Sph 1-P-induced endothelial barrier enhancement would attenuate lung edema formation in a gnawing model of pure ventilator-induced lung injury as well as decrease regional vascular leak in a clinically relevant canine example of LPS-induced, ventilator-associated ALI. Our deductions strongly support further consideration of Sph 1-P as a novel therapeutic intervention for ALL one of the results of these studies have been previously published in abstract form (16 17)

METHODS

John Hopkins University Institutional Animal Care and Use Committee approved all animal protocols. Additional [i]modus operandi[/i] details are reported in the online supplement

Mouse Ventilator-induced Lung Injury Preparation

C57BL/6 mice were anesthetized and tracheostomized, and the jugular vein was cannulated. Mice were treated with intravenous saline or Sph 1-P (Sigma Co St Louis, MO) and 2 hours of high-VT (17 cc/kg) mechanical ventilation. Lung capillary leakage in mice was assessed using Evans gloomy dye extravasation as we previously described (13)