title: The impact of low-frequency, low-force cyclic stretching of human bronchi on airway responsiveness.
abstract: In vivo, the airways are constantly subjected to oscillatory strain (due to tidal breathing during spontaneous respiration) and (in the event of mechanical ventilation) positive pressure. This exposure is especially problematic for the cartilage-free bronchial tree. The effects of cyclic stretching (other than high-force stretching) have not been extensively characterized. Hence, the objective of the present study was to investigate the functional and transcriptional response of human bronchi to repetitive mechanical stress caused by low-frequency, low-force cyclic stretching.
  
  
  
  After preparation and equilibration in an organ bath, human bronchial rings from 66 thoracic surgery patients were stretched in 1-min cycles of elongation and relaxation over a 60-min period. For each segment, the maximal tension corresponded to 80% of the reference contraction (the response to 3 mM acetylcholine). The impact of cyclic stretching (relative to non-stretched controls) was examined by performing functional assessments (epithelium removal and incubation with sodium channel agonists/antagonists or inhibitors of intracellular pathways), biochemical assays of the organ bath fluid (for detecting the release of pro-inflammatory cytokines), and RT-PCR assays of RNA isolated from tissue samples.
  
  
  
  The application of low-force cyclic stretching to human bronchial rings for 60 min resulted in an immediate, significant increase in bronchial basal tone, relative to non-cyclic stretching (4.24 ± 0.16 g vs. 3.28 ± 0.12 g, respectively; p < 0.001). This cyclic stimulus also increased the affinity for acetylcholine (-log EC50: 5.67 ± 0.07 vs. 5.32 ± 0.07, respectively; p p < 0.001). Removal of airway epithelium and pretreatment with the Rho-kinase inhibitor Y27632 and inward-rectifier K+ or L-type Ca2+channel inhibitors significantly modified the basal tone response. Exposure to L-NAME had opposing effects in all cases. Pro-inflammatory pathways were not involved in the response; cyclic stretching up-regulated the early mRNA expression of MMP9 only, and was not associated with changes in organ bath levels of pro-inflammatory mediators.
  
  
  
  Low-frequency, low-force cyclic stretching of whole human bronchi induced a myogenic response rather than activation of the pro-inflammatory signaling pathways mediated by mechanotransduction.
authors.affiliation: Laboratory of Research in Respiratory Pharmacology - UPRES EA220, Université Versailles - Saint-Quentin, 11 rue Guillaume Lenoir, F-92150, Suresnes, France. m.leguen@hopital-foch.org.|Department of Anesthesiology, Hôpital Foch, Université Versailles - Saint-Quentin, Suresnes, France. m.leguen@hopital-foch.org.
authors.forename: Morgan
authors.initials: M
authors.lastname: Le Guen
authors.affiliation: Laboratory of Research in Respiratory Pharmacology - UPRES EA220, Université Versailles - Saint-Quentin, 11 rue Guillaume Lenoir, F-92150, Suresnes, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Grassin-Delyle
authors.affiliation: Laboratory of Research in Respiratory Pharmacology - UPRES EA220, Université Versailles - Saint-Quentin, 11 rue Guillaume Lenoir, F-92150, Suresnes, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Naline
authors.affiliation: Laboratory of Research in Respiratory Pharmacology - UPRES EA220, Université Versailles - Saint-Quentin, 11 rue Guillaume Lenoir, F-92150, Suresnes, France.
authors.forename: Amparo
authors.initials: A
authors.lastname: Buenestado
authors.affiliation: Laboratory of Research in Respiratory Pharmacology - UPRES EA220, Université Versailles - Saint-Quentin, 11 rue Guillaume Lenoir, F-92150, Suresnes, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Brollo
authors.affiliation: Department of Pathology, Hôpital Foch, Suresnes, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Longchampt
authors.affiliation: Department of Thoracic Surgery, Centre Médico-Chirurgical du Val d'Or, Saint-Cloud, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Kleinmann
authors.affiliation: Laboratory of Research in Respiratory Pharmacology - UPRES EA220, Université Versailles - Saint-Quentin, 11 rue Guillaume Lenoir, F-92150, Suresnes, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Devillier
authors.affiliation: Laboratory of Research in Respiratory Pharmacology - UPRES EA220, Université Versailles - Saint-Quentin, 11 rue Guillaume Lenoir, F-92150, Suresnes, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Faisy
mesh_terms: D000368:Aged; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D040542:Mechanotransduction, Cellular / Q000187:drug effects; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D011661:Pulmonary Stretch Receptors / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013314:Stress, Mechanical; D013997:Time Factors; D014158:Transcription, Genetic
chemical_list: D016207:Cytokines; D012333:RNA, Messenger
keywords: Airway hyperresponsiveness; Cyclic stretching; Human bronchus; Mechanical ventilation