American journal of respiratory cell and molecular biology
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Am. J. Respir. Cell Mol. Biol. · May 2011
Surfactant protein D deficiency increases lung injury during endotoxemia.
Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are major causes of acute respiratory failure with high rates of morbidity and mortality. Although surfactant protein (SP)-D plays a critical role in pulmonary innate immunity and several clinical studies suggest that this protein may be implicated in the pathophysiology of ARDS, little is known regarding the function of SP-D in ARDS. In the present study, we induced indirect lung injury by intraperitoneal injection of LPS and direct lung injury by intratracheal injection of LPS in wild-type and Sftpd(-/-) mice to elucidate the role of SP-D during ALI/ARDS. ⋯ In contrast, after direct injury, the concentration of GM-CSF was 20-fold less in Sftpd(-/-) mice than wild-type mice. Despite increased inflammatory cells and markers of inflammation, survival in Sftpd(-/-) mice after indirect lung injury was paradoxically increased. In conclusion, these results suggest that SP-D inhibits pulmonary inflammation and migration of peripheral monocyte/macrophages into the lung through GM-CSF-dependent pathways during indirect lung injury.
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Am. J. Respir. Cell Mol. Biol. · Apr 2011
A potential role for P2X7R in allergic airway inflammation in mice and humans.
P2X₇R deficiency is associated with a less severe outcome in acute and chronic inflammatory disorders. Recently, we demonstrated that extracellular adenosine triphosphate is involved in the pathogenesis of asthma by modulating the function of dendritic cells (DCs). However, the role of the purinergic receptor subtype P2X₇ is unknown. ⋯ In the DC-driven model of AAI, P2X₇R-deficient DCs showed a reduced capacity to induce Th2 immunity in vivo. Up-regulation of P2X₇R on BAL macrophages and blood eosinophils could be observed in patients with chronic asthma. Our data suggest that targeting P2X₇R on hematopoietic cells (e.g., DCs or eosinophils) might be a new therapeutic option for the treatment of asthma.
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Am. J. Respir. Cell Mol. Biol. · Apr 2011
Ablation of glutaredoxin-1 attenuates lipopolysaccharide-induced lung inflammation and alveolar macrophage activation.
Protein S-glutathionylation (PSSG), a reversible posttranslational modification of reactive cysteines, recently emerged as a regulatory mechanism that affects diverse cell-signaling cascades. The extent of cellular PSSG is controlled by the oxidoreductase glutaredoxin-1 (Grx1), a cytosolic enzyme that specifically de-glutathionylates proteins. Here, we sought to evaluate the impact of the genetic ablation of Grx1 on PSSG and on LPS-induced lung inflammation. ⋯ We also demonstrated that PSSG reactivity was prominent in alveolar macrophages (AMs). Comparative BAL analyses from WT and Glrx1(-/-) mice revealed fewer and smaller AMs in Glrx1(-/-) mice, which showed a significantly decreased expression of NF-κB family members, impaired nuclear translocation of RelA, and lower levels of NF-κB-dependent cytokines after exposure to LPS, compared with WT cells. Taken together, these results indicate that Grx1 regulates the production of inflammatory mediators through control of S-glutathionylation-sensitive signaling pathways such as NF-κB, and that Grx1 expression is critical to the activation of AMs.
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Am. J. Respir. Cell Mol. Biol. · Apr 2011
Simvastatin improves epithelial dysfunction and airway hyperresponsiveness: from asymmetric dimethyl-arginine to asthma.
Altered arginine metabolism, the uncoupling of nitric oxide synthase (NOS) by asymmetric dimethyl-arginine (ADMA), increased oxo-nitrosative stress, and cellular injury were reported in airway epithelial cells in asthma. Statins improve vascular endothelial dysfunction by reducing ADMA and increasing endothelial NOS (eNOS), thereby reducing oxo-nitrosative stress in cardiovascular diseases. Whether statin therapy leads to similar beneficial effects in lung epithelium in asthma is unknown. ⋯ Cell injury markers such as cytosolic cytochrome c, caspases 3 and 9 and apoptotic protease activating factor 1 (Apaf-1) were also reduced. Simvastatin improves dysfunctional nitric oxide metabolism in allergically inflamed lungs. Important pleiotropic mechanisms may be responsible for the statin-induced reduction of airway inflammation, epithelial injury, and airway hyperresponsiveness.
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Am. J. Respir. Cell Mol. Biol. · Mar 2011
Protective properties of inhaled IL-22 in a model of ventilator-induced lung injury.
High-pressure ventilation induces barotrauma and pulmonary inflammation, thus leading to ventilator-induced lung injury (VILI). IL-22 has both immunoregulatory and tissue-protective properties. Functional IL-22 receptor expression is restricted to nonleukocytic cells, such as alveolar epithelial cells. ⋯ IL-22 reduced VILI-associated biotrauma (i.e., pulmonary concentrations of macrophage inflammatory protein-2, IL-6, and matrix metalloproteinase 9) and mediated pulmonary STAT3/SOCS3 activation. In addition, despite a short observation period of 4 hours, inhaled IL-22 resulted in an improved survival of the rats. These data support the hypothesis that IL-22, likely via activation of STAT3 and downstream genes (e.g., SOCS3), is able to protect against cell stretch and pulmonary baro-/biotrauma by enhancing epithelial cell resistibility.