title: 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.
authors.affiliation: Department of Internal Medicine-Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA. Wake Forest Critical Illness, Injury and Recovery Research Center, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA. dfiles@wakehealth.edu.
authors.forename: D Clark
authors.initials: DC
authors.lastname: Files
authors.affiliation: Department of Internal Medicine-Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Chun
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Internal Medicine-Gerontology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA. National Scientific and Technical Research Council (CONICET) and School of Medicine, National University of La Plata, 1900 La Plata, Argentina.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pereyra
authors.affiliation: Department of Internal Medicine-Gerontology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Zhong-Min
authors.initials: ZM
authors.lastname: Wang
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins Asthma and Allergy Center, Baltimore, MD 21205, USA.
authors.forename: Neil R
authors.initials: NR
authors.lastname: Aggarwal
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins Asthma and Allergy Center, Baltimore, MD 21205, USA.
authors.forename: Franco R
authors.initials: FR
authors.lastname: D'Alessio
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins Asthma and Allergy Center, Baltimore, MD 21205, USA.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Garibaldi
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins Asthma and Allergy Center, Baltimore, MD 21205, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Mock
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins Asthma and Allergy Center, Baltimore, MD 21205, USA.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Singer
authors.affiliation: Department of Otolaryngology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Feng
authors.affiliation: Department of Internal Medicine-Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Raghunatha R
authors.initials: RR
authors.lastname: Yammani
authors.affiliation: Department of Internal Medicine-Gerontology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Tan
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine-Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine-Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Sydney
authors.initials: S
authors.lastname: Philpott
authors.affiliation: Department of Internal Medicine-Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Lussier
authors.affiliation: Department of Internal Medicine-Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Lina
authors.initials: L
authors.lastname: Purcell
authors.affiliation: Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Chou
authors.affiliation: Department of Internal Medicine-Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA. Wake Forest Critical Illness, Injury and Recovery Research Center, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Seeds
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins Asthma and Allergy Center, Baltimore, MD 21205, USA.
authors.forename: Landon S
authors.initials: LS
authors.lastname: King
authors.affiliation: Department of Internal Medicine-Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA. Wake Forest Critical Illness, Injury and Recovery Research Center, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Morris
authors.affiliation: Department of Internal Medicine-Gerontology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Delbono
mesh_terms: D055371:Acute Lung Injury / Q000097:blood / Q000150:complications / Q000473:pathology* / Q000628:therapy*; D000818:Animals; D018925:Chemokines / Q000378:metabolism; D005081:Exercise Therapy; D016179:Granulocyte Colony-Stimulating Factor / Q000097:blood / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008070:Lipopolysaccharides; D008810:Mice, Inbred C57BL; D009043:Motor Activity; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000473:pathology*; D009133:Muscular Atrophy / Q000473:pathology; D009504:Neutrophils / Q000378:metabolism*; D010805:Physical Conditioning, Animal; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D012128:Respiratory Distress Syndrome / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D019282:Wasting Syndrome / Q000097:blood / Q000150:complications / Q000473:pathology*
chemical_list: D018925:Chemokines; D008070:Lipopolysaccharides; D009124:Muscle Proteins; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D000070584:Tripartite Motif Proteins; D016179:Granulocyte Colony-Stimulating Factor; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases