Therapeutic exercise attenuates neutrophilic lung injury and skeletal muscle wasting

Early mobilization of critically ill patients with the acute respiratory distress syndrome (ARDS) has emerged as a therapeutic strategy that improves patient outcomes, such as the duration of mechanical ventilation and muscle strength. Despite the apparent efficacy of early mobility programs, their use in clinical practice is limited outside of specialized centers and clinical trials. To evaluate the mechanisms underlying mobility therapy, we exercised acute lung injury (ALI) mice for 2 days after the instillation of lipopolysaccharides into their lungs. We found that a short duration of moderate intensity exercise in ALI mice attenuated muscle ring finger 1 (MuRF1)?mediated atrophy of the limb and respiratory muscles and improved limb muscle force generation. Exercise also limited the influx of neutrophils into the alveolar space through modulation of a coordinated systemic neutrophil chemokine response. Granulocyte colony-stimulating factor (G-CSF) concentrations were systemically reduced by exercise in ALI mice, and in vivo blockade of the G-CSF receptor recapitulated the lung exercise phenotype in ALI mice. Additionally, plasma G-CSF concentrations in humans with acute respiratory failure (ARF) undergoing early mobility therapy showed greater decrements over time compared to control ARF patients. Together, these data provide a mechanism whereby early mobility therapy attenuates muscle wasting and limits ongoing alveolar neutrophilia through modulation of systemic neutrophil chemokines in lung-injured mice and humans.Fil: Files, D. Clark. School Of Medicine; Estados UnidosFil: Liu, Chun. School Of Medicine; Estados UnidosFil: Pereyra, Andrea Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Wang, Zhong Min. University Wake Forest; Estados Unidos. School Of Medicine; Estados UnidosFil: Aggarwal, Neil. Johns Hopkins Asthma And Allergy Center; Estados UnidosFil: D´Alessio, Franco. Johns Hopkins Asthma And Allergy Center; Estados UnidosFil: Garibaldi, Brian T.. Johns Hopkins Asthma and Allergy Center; Estados UnidosFil: Mock, Jason R.. Johns Hopkins Asthma and Allergy Center; Estados UnidosFil: Singer, Benjamin D.. Johns Hopkins Asthma and Allergy Center; Estados UnidosFil: Feng, Xin. Wake Forest School of Medicine; Estados UnidosFil: Yammani, Raghunatha R.. Wake Forest School of Medicine; Estados UnidosFil: Zhang, Tan. Wake Forest School of Medicine; Estados UnidosFil: Lee, Amy L.. Wake Forest School of Medicine; Estados UnidosFil: Philpott, Sydney. Wake Forest School of Medicine; Estados UnidosFil: Lussier, Stephanie. Wake Forest School of Medicine; Estados UnidosFil: Purcell, Lina. Wake Forest School of Medicine; Estados UnidosFil: Chou, Jeff. Wake Forest School of Medicine; Estados UnidosFil: Seeds, Michael. Wake Forest School of Medicine; Estados UnidosFil: King, Landon S.. Johns Hopkins Asthma and Allergy Center; Estados UnidosFil: Morris, Peter E.. Wake Forest School of Medicine; Estados UnidosFil: Delbono, Osvaldo. School Of Medicine; Estados Unido

Therapeutic exercise attenuates neutrophilic lung injury and skeletal muscle wasting

Early mobilization of critically ill patients with the acute respiratory distress syndrome (ARDS) has emerged as a therapeutic strategy that improves patient outcomes, such as the duration of mechanical ventilation and muscle strength. Despite the apparent efficacy of early mobility programs, their use in clinical practice is limited outside of specialized centers and clinical trials. To evaluate the mechanisms underlying mobility therapy, we exercised acute lung injury (ALI) mice for 2 days after the instillation of lipopolysaccharides into their lungs. We found that a short duration of moderate intensity exercise in ALI mice attenuated muscle ring finger 1 (MuRF1)–mediated atrophy of the limb and respiratory muscles and improved limb muscle force generation. Exercise also limited the influx of neutrophils into the alveolar space through modulation of a coordinated systemic neutrophil chemokine response. Granulocyte colony-stimulating factor (G-CSF) concentrations were systemically reduced by exercise in ALI mice, and in vivo blockade of the G-CSF receptor recapitulated the lung exercise phenotype in ALI mice. Additionally, plasma G-CSF concentrations in humans with acute respiratory failure (ARF) undergoing early mobility therapy showed greater decrements over time compared to control ARF patients. Together, these data provide a mechanism whereby early mobility therapy attenuates muscle wasting and limits ongoing alveolar neutrophilia through modulation of systemic neutrophil chemokines in lung-injured mice and humans.Facultad de Ciencias Médica

Estradiol resolves pneumonia via ERβ in regulatory T cells

Current treatments for pneumonia (PNA) are focused on the pathogens. Mortality from PNA-induced acute lung injury (PNA-ALI) remains high, underscoring the need for additional therapeutic targets. Clinical and experimental evidence exists for potential sex differences in PNA survival, with males having higher mortality. In a model of severe pneumococcal PNA, when compared with male mice, age-matched female mice exhibited enhanced resolution characterized by decreased alveolar and lung inflammation and increased numbers of Tregs. Recognizing the critical role of Tregs in lung injury resolution, we evaluated whether improved outcomes in female mice were due to estradiol (E2) effects on Treg biology. E2 promoted a Treg-suppressive phenotype in vitro and resolution of PNA in vivo. Systemic rescue administration of E2 promoted resolution of PNA in male mice independent of lung bacterial clearance. E2 augmented Treg expression of Foxp3, CD25, and GATA3, an effect that required ERβ, and not ERα, signaling. Importantly, the in vivo therapeutic effects of E2 were lost in Treg-depleted mice (Foxp3DTR mice). Adoptive transfer of ex vivo E2-treated Tregs rescued Streptococcus pneumoniae–induce PNA-ALI, a salutary effect that required Treg ERβ expression. E2/ERβ was required for Tregs to control macrophage proinflammatory responses. Our findings support the therapeutic role for E2 in promoting resolution of lung inflammation after PNA via ERβ Tregs

Low-Dose Oxygen Enhances Macrophage-Derived Bacterial Clearance following Cigarette Smoke Exposure

Background. Chronic obstructive pulmonary disease (COPD) is a common, smoking-related lung disease. Patients with COPD frequently suffer disease exacerbations induced by bacterial respiratory infections, suggestive of impaired innate immunity. Low-dose oxygen is a mainstay of therapy during COPD exacerbations; yet we understand little about whether oxygen can modulate the effects of cigarette smoke on lung immunity. Methods. Wild-type mice were exposed to cigarette smoke for 5 weeks, followed by intratracheal instillation of Pseudomonas aeruginosa (PAO1) and 21% or 35–40% oxygen. After two days, lungs were harvested for PAO1 CFUs, and bronchoalveolar fluid was sampled for inflammatory markers. In culture, macrophages were exposed to cigarette smoke and oxygen (40%) for 24 hours and then incubated with PAO1, followed by quantification of bacterial phagocytosis and inflammatory markers. Results. Mice exposed to 35–40% oxygen after cigarette smoke and PAO1 had improved survival and reduced lung CFUs and inflammation. Macrophages from these mice expressed less TNF-α and more scavenger receptors. In culture, macrophages exposed to cigarette smoke and oxygen also demonstrated decreased TNF-α secretion and enhanced phagocytosis of PAO1 bacteria. Conclusions. Our findings demonstrate a novel, protective role for low-dose oxygen following cigarette smoke and bacteria exposure that may be mediated by enhanced macrophage phagocytosis