Effect of adrenalectomy on pulmonary edema resolution

Purpose: The capacity of the lung to clear edema fluid has been shown to be one of the factors that can influence the prognosis of cardiogenic and noncardiogenic pulmonary edema. Active Na+ transport across the alveolar epithelium is the main driving force involved in this physiological process. Since endogenous catecholamines are known to activate the sodium-dependent mechanism of alveolar edema clearance, the objective of the present study was to explore if adrenalectomy, which prevents the release of endogenous catecholamines and other hormones, such as corticosterone, into circulation, would affect edema resolution in a model of lung injury induced by thiourea. Methods: A high-permeability pulmonary edema was induced in adult male Sprague-Dawley rats using a thiourea-induced pulmonary edema model. To determine if the release of adrenalin and corticosterone is essential for resolution of the thiourea-induced edema, we measured 1) the release of adrenalin and corticosterone in urine and 2) edema resolution in control animals and adrenalectomized animals. Results: The administration of thiourea significantly increased the wet-to-dry ratio after four and eight hours. After 12 and 24 hours, the wet-to-dry ratio gradually returned to baseline. Although thiourea-induced pulmonary edema was associated with a significant increase in urine adrenalin and corticosterone, the absence of adrenalin and corticosterone response in adrenalectomized animals did not prevent the resolution of the edema. Conclusions: These experiments demonstrated that resolution of thioureainduced pulmonary edema can occur in the absence of hormonal secretion by the adrenal glands.

Lymphocytic choriomeningitis virus Clone 13 infection causes either persistence or acute death dependent on IFN-1, cytotoxic T lymphocytes (CTLs), and host genetics

Understanding of T cell exhaustion and successful therapy to restore T cell function was first described using Clone (Cl) 13 variant selected from the lymphocytic choriomeningitis virus (LCMV) Armstrong (ARM) 53b parental strain. T cell exhaustion plays a pivotal role in both persistent infections and cancers of mice and humans. C57BL/6, BALB, SWR/J, A/J, 129, C3H, and all but one collaborative cross (CC) mouse strain following Cl 13 infection have immunosuppressed T cell responses, high PD-1, and viral titers leading to persistent infection and normal life spans. In contrast, the profile of FVB/N, NZB, PL/J, SL/J, and CC NZO mice challenged with Cl 13 is a robust T cell response, high titers of virus, PD-1, and Lag3 markers on T cells. These mice all die 7 to 9 d after Cl 13 infection. Death is due to enhanced pulmonary endothelial vascular permeability, pulmonary edema, collapse of alveolar air spaces, and respiratory failure. Pathogenesis involves abundant levels of Cl 13 receptor alpha-dystroglycan on endothelial cells, with high viral replication in such cells leading to immunopathologic injury. Death is aborted by blockade of interferon-1 (IFN-1) signaling or deletion of CD8 T cells.

Sphingomyelin synthase 2 (SMS2) deficiency attenuates LPS-induced lung injury

Sphingomyelin synthase (SMS) catalyzes the synthesis of sphingomyelin (SM) and is required for maintenance of plasma membrane microdomain fluidity. Of the two isoforms of mammalian SMS, SMS1 is mostly present in the trans-Golgi apparatus, whereas SMS2 is predominantly found at the plasma membrane. SMS2 has a role in receptor mediated response to inflammation in macrophages, however, the role of SMS2 in vascular permeability, pulmonary edema, and lung injury have not been investigated. To define the role of SMS activation in lung injury, we utilized a lipopolysaccharide (LPS)-induced lung edema model. SMS activity was measured and correlated with the severity of lung injury. Within 4 h of LPS treatment, SMS activity was increased significantly and remained upregulated up to 24 h. Comparison of LPS-induced lung injury in SMS2 knockout (SMS2−/−) and wild-type littermate control mice showed that inflammation, cytokine induction, and lung injury were significantly inhibited in SMS2−/− mice. Our results suggest that a deficiency of SMS2 can diminish the extent of pulmonary edema and lung injury. Furthermore, we show that depletion of SMS2 was sufficient to decrease MAP kinase-JNK activation, severity of LPS-induced pulmonary neutrophil influx, and inflammation, suggesting a novel role of SMS2 activation in lung injury.