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Therapeutic exercise attenuates neutrophilic lung injury and skeletal muscle wasting.

Abstract
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.
AuthorsD Clark Files, Chun Liu, Andrea Pereyra, Zhong-Min Wang, Neil R Aggarwal, Franco R D'Alessio, Brian T Garibaldi, Jason R Mock, Benjamin D Singer, Xin Feng, Raghunatha R Yammani, Tan Zhang, Amy L Lee, Sydney Philpott, Stephanie Lussier, Lina Purcell, Jeff Chou, Michael Seeds, Landon S King, Peter E Morris, Osvaldo Delbono
JournalScience translational medicine (Sci Transl Med) Vol. 7 Issue 278 Pg. 278ra32 (Mar 11 2015) ISSN: 1946-6242 [Electronic] United States
PMID25761888 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015, American Association for the Advancement of Science.
Chemical References
  • Chemokines
  • Lipopolysaccharides
  • Muscle Proteins
  • Receptors, Granulocyte Colony-Stimulating Factor
  • Tripartite Motif Proteins
  • Granulocyte Colony-Stimulating Factor
  • Trim63 protein, mouse
  • Ubiquitin-Protein Ligases
Topics
  • Acute Lung Injury (blood, complications, pathology, therapy)
  • Animals
  • Chemokines (metabolism)
  • Exercise Therapy
  • Granulocyte Colony-Stimulating Factor (blood, metabolism)
  • Humans
  • Inflammation (pathology)
  • Lipopolysaccharides
  • Mice, Inbred C57BL
  • Motor Activity
  • Muscle Proteins (metabolism)
  • Muscle, Skeletal (pathology)
  • Muscular Atrophy (pathology)
  • Neutrophils (metabolism)
  • Physical Conditioning, Animal
  • Pulmonary Alveoli (metabolism, pathology)
  • Receptors, Granulocyte Colony-Stimulating Factor (metabolism)
  • Respiratory Distress Syndrome (metabolism, pathology)
  • Time Factors
  • Tripartite Motif Proteins
  • Ubiquitin-Protein Ligases (metabolism)
  • Wasting Syndrome (blood, complications, pathology)

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