Tiotropium bromide suppresses smoke inhalation and burn injury-induced ERK 1/2 and SMAD 2/3 signaling in sheep bronchial submucosal glands

Abstract The effects of tiotropium bromide on ERK 1/2, SMAD 2/3 and NFκB signaling in bronchial submucosal gland (SMG) cells of sheep after smoke inhalation and burn injury (S + B) were studied. We hypothesized that tiotropium would modify intracellular signaling processes within SMG cells after injury. Bronchial tissues were obtained from uninjured (sham, n = 6), S + B injured sheep 48 h after injury (n = 6), and injured sheep nebulized with tiotropium (n = 6). The percentage (mean ± SD) of cells showing nuclear localization of phosphorylated ERK 1/2, pSMAD 2/3, and NFκB (p65) was determined by immunohistochemistry. Nuclear pERK 1/2 staining was increased in injured animals as compared to sham, (66 ± 20 versus 14 ± 9), p = 0.0022, as was nuclear pSMAD, 84 ± 10 versus 20 ± 10, p = 0.0022. There was a significant decrease in pERK 1/2 labeling in the tiotropium group compared to the injured group (31 ± 20 versus 66 ± 20, p = 0.013), and also a decrease in pSMAD labeling, 62 ± 17 versus 84 ± 10, p = 0.04. A significant increase for NFκB (p65) was noted in injured animals as compared to sham (73 ± 16 versus 7 ± 6, p = 0.0022). Tiotropium-treated animals showed decreased p65 labeling as compared to injured (35 ± 17 versus 74 ± 16, p = 0.02). The decrease in nuclear expression of pERK, pSMAD and NFκB molecules in SMG cells with tiotropium treatment is suggestive that their activation after injury is mediated in part through muscarinic receptors.

[1]  D. Herndon,et al.  Effect of Bronchodilators on Bronchial Gland Cell Proliferation After Inhalation and Burn Injury in Sheep , 2013, Journal of burn care & research : official publication of the American Burn Association.

[2]  G. Downey,et al.  Human epidermal growth factor receptor signaling in acute lung injury. , 2012, American journal of respiratory cell and molecular biology.

[3]  M. Hollenberg,et al.  The EGF Receptor and HER2 Participate in TNF-α-Dependent MAPK Activation and IL-8 Secretion in Intestinal Epithelial Cells , 2012, Mediators of inflammation.

[4]  D. Herndon,et al.  Assessment of Combined Muscarinic Antagonist and Fibrinolytic Therapy for Inhalation Injury , 2012, Journal of burn care & research : official publication of the American Burn Association.

[5]  Jianjing Xue,et al.  LPS-binding Protein Enables Intestinal Epithelial Restitution Despite LPS Exposure , 2012, Journal of pediatric gastroenterology and nutrition.

[6]  S. Szabó,et al.  Molecular Mechanisms of Basic Fibroblast Growth Factor Effect on Healing of Ulcerative Colitis in Rats , 2011, Journal of Pharmacology and Experimental Therapeutics.

[7]  R. Gilchrist,et al.  Differences in the participation of TGFB superfamily signalling pathways mediating porcine and murine cumulus cell expansion. , 2011, Reproduction.

[8]  Dan Xu,et al.  Role of extracellular signal-regulated kinase 1/2 in cigarette smoke-induced mucus hypersecretion in a rat model. , 2011, Chinese medical journal.

[9]  A. Schmeling,et al.  Delayed asphyxia due to inhalation injury , 2011, International Journal of Legal Medicine.

[10]  A. Gillissen,et al.  Inhibition of granulocyte migration by tiotropium bromide , 2011, Respiratory research.

[11]  Edward R. Kraft,et al.  Muscarinic receptor antagonist therapy improves acute pulmonary dysfunction after smoke inhalation injury in sheep , 2010, Critical care medicine.

[12]  D. Herndon,et al.  Acute secretory cell toxicity and epithelial exfoliation after smoke inhalation injury in sheep: An electron and light microscopic study , 2010, Toxicology mechanisms and methods.

[13]  A. Ammit,et al.  Development of inhalable formulations of anti-inflammatory drugs to potentially treat smoke inhalation injury in burn victims. , 2010, International journal of pharmaceutics.

[14]  福地 一典,et al.  Muscarinic receptor antagonist , 2010 .

[15]  M. Profita,et al.  Chronic obstructive pulmonary disease and neutrophil infiltration: role of cigarette smoke and cyclooxygenase products. , 2010, American journal of physiology. Lung cellular and molecular physiology.

[16]  P. Fernández-Salguero,et al.  Role of transforming growth factor β in cancer microenvironment , 2009 .

[17]  E. Bateman,et al.  Alternative mechanisms for tiotropium. , 2009, Pulmonary pharmacology & therapeutics.

[18]  P. Fernández-Salguero,et al.  Role of transforming growth factor beta in cancer microenvironment. , 2009, Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico.

[19]  L. Cancio.  Airway management and smoke inhalation injury in the burn patient. , 2009, Clinics in plastic surgery.

[20]  P. Casarosa,et al.  Smoke, Choline Acetyltransferase, Muscarinic Receptors, and Fibroblast Proliferation in Chronic Obstructive Pulmonary Disease , 2009, Journal of Pharmacology and Experimental Therapeutics.

[21]  L. Wollin,et al.  Tiotropium bromide exerts anti-inflammatory activity in a cigarette smoke mouse model of COPD. , 2009, Pulmonary pharmacology & therapeutics.

[22]  P. Burgel,et al.  Epidermal growth factor receptor-mediated innate immune responses and their roles in airway diseases , 2008, European Respiratory Journal.

[23]  J. Engelhardt,et al.  The glandular stem/progenitor cell niche in airway development and repair. , 2008, Proceedings of the American Thoracic Society.

[24]  M. S. Katz,et al.  Distinct pathways of ERK activation by the muscarinic agonists pilocarpine and carbachol in a human salivary cell line. , 2008, American journal of physiology. Cell physiology.

[25]  R. Demling,et al.  Smoke Inhalation Lung Injury: An Update , 2008, Eplasty.

[26]  M. Profita,et al.  Acetylcholine mediates the release of IL-8 in human bronchial epithelial cells by a NFkB/ERK-dependent mechanism. , 2008, European journal of pharmacology.

[27]  T. Welte,et al.  Tiotropium suppresses acetylcholine-induced release of chemotactic mediators in vitro. , 2007, Respiratory medicine.

[28]  D. Herndon,et al.  Production of pro-inflammatory polypeptides by airway mucous glands and its potential significance. , 2007, Pulmonary pharmacology & therapeutics.

[29]  D. Edelman,et al.  Pneumonia After Inhalation Injury , 2007, Journal of burn care & research : official publication of the American Burn Association.

[30]  D. Edelman,et al.  Factors Affecting Prognosis of Inhalation Injury , 2006, Journal of burn care & research : official publication of the American Burn Association.

[31]  D. Greenhalgh,et al.  Continuous nebulized albuterol attenuates acute lung injury in an ovine model of combined burn and smoke inhalation* , 2006, Critical care medicine.

[32]  R. Gamelli,et al.  Effect of blood transfusion on outcome after major burn injury: A multicenter study* , 2006, Critical care medicine.

[33]  K. Racké,et al.  Control by cholinergic mechanisms. , 2006, European journal of pharmacology.

[34]  G. Bae,et al.  Cooperation of H2O2-mediated ERK activation with Smad pathway in TGF-beta1 induction of p21WAF1/Cip1. , 2006, Cellular signalling.

[35]  Wiley Interscience,et al.  Cystic fibrosis and airway submucosal glands , 2005, Pediatric pulmonology.

[36]  J. Zwischenberger,et al.  ACUTE BRONCHIAL OBSTRUCTION IN SHEEP: HISTOPATHOLOGY AND GLAND CYTOKINE EXPRESSION , 2005, Experimental lung research.

[37]  M. White,et al.  Stimulus-Coupled Spatial Restriction of Extracellular Signal-Regulated Kinase 1/2 Activity Contributes to the Specificity of Signal-Response Pathways , 2004, Molecular and Cellular Biology.

[38]  K. Racké,et al.  The airway cholinergic system: physiology and pharmacology. , 2004, Pulmonary pharmacology & therapeutics.

[39]  L. DiPietro,et al.  Neutrophil function in the healing wound: adding insult to injury? , 2004, Thrombosis and Haemostasis.

[40]  Kazunori Murakami,et al.  Airway obstruction in sheep with burn and smoke inhalation injuries. , 2003, American journal of respiratory cell and molecular biology.

[41]  H. Schnaper,et al.  Cross‐talk between ERK MAP kinase and Smad‐signaling pathways enhances TGF‐β dependent responses in human mesangial cells , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[42]  L. DiPietro,et al.  Accelerated wound closure in neutrophil‐depleted mice , 2003, Journal of leukocyte biology.

[43]  H. Nakae,et al.  Failure to clear casts and secretions following inhalation injury can be dangerous: report of a case. , 2001, Burns : journal of the International Society for Burn Injuries.

[44]  J. Widdicombe,et al.  A comparative study of mammalian tracheal mucous glands , 2000, Journal of anatomy.

[45]  E. Nishida,et al.  A Novel Regulatory Mechanism in the Mitogen-activated Protein (MAP) Kinase Cascade , 1997, The Journal of Biological Chemistry.

[46]  E. Nishida,et al.  Interaction of MAP kinase with MAP kinase kinase: its possible role in the control of nucleocytoplasmic transport of MAP kinase , 1997, The EMBO journal.

[47]  A. Miyajima.  Cytokine regulation: an overview. , 1997, Leukemia.

[48]  P. Barnes,et al.  Muscarinic receptor subtypes in airways. , 1993, Trends in pharmacological sciences.

[49]  T. Kishimoto,et al.  Cytokine receptors and signal transduction , 1992, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[50]  M. Ebina,et al.  Marked goblet cell hyperplasia with mucus accumulation in the airways of patients who died of severe acute asthma attack. , 1992, Chest.

[51]  H. Sasaki,et al.  Muscarinic receptor subtypes in feline tracheal submucosal gland secretion. , 1992, The American journal of physiology.

[52]  P. Barnes,et al.  Autoradiographic visualization of muscarinic receptor subtypes in human and guinea pig lung. , 1990, The American review of respiratory disease.

[53]  P. Barnes,et al.  Muscarinic receptor subtypes in human and guinea pig lung. , 1989, European journal of pharmacology.

[54]  P. Barnes,et al.  Mapping of adrenergic receptors in the trachea by autoradiography. , 1983, Experimental lung research.

[55]  P. Barnes,et al.  Muscarinic receptors in lung and trachea: autoradiographic localization using [3H]quinuclidinyl benzilate. , 1982, European journal of pharmacology.

[56]  S. Pietak,et al.  Airway obstruction following smoke inhalation. , 1976, Canadian Medical Association journal.

[57]  J. Galway.  Airway obstruction , 1972, Anaesthesia.

[58]  J. Sturgess,et al.  A reconstruction of the duct system and secretory tubules of the human bronchial submucosal gland , 1969, Thorax.

[59]  哲郎 小林,et al.  急速に進行増大した epidermal growth factor receptor陽性乳腺扁平上皮癌の１例 , 2013 .

[60]  A. Sciuto,et al.  ToxiC inhalaTional injury and ToxiC indusTrial ChemiCals , 2009 .

[61]  J. Parkb,et al.  Cooperation of H 2 O 2-mediated ERK activation with Smad pathway in TGF-h 1 induction of p 21 WAF 1 / Cip 1 , 2005 .

[62]  R. Barrow,et al.  Cellular sequence of tracheal repair in sheep after smoke inhalation injury , 2004, Lung.

[63]  R. Jorissen,et al.  Epidermal growth factor receptor , 2003 .

[64]  P. Burgel,et al.  Activation of epidermal growth factor receptors is responsible for mucin synthesis induced by cigarette smoke. , 2001, American journal of physiology. Lung cellular and molecular physiology.

[65]  A. Wells.  EGF receptor. , 1999, The international journal of biochemistry & cell biology.

[66]  P. Barnes.  Muscarinic receptor subtypes: implications for therapy. , 1993, Agents and actions. Supplements.

[67]  Evon M. O. Abu-Taieh,et al.  Comparative Study , 2020, Definitions.

[68]  H. Herschman,et al.  7 – The EGF Receptor , 1985 .

[69]  K. Asano,et al.  International Journal of Chronic Obstructive Pulmonary Disease Dovepress Tiotropium Bromide Inhibits Tgf-β-induced Mmp Production from Lung Fibroblasts by Interfering with Smad and Mapk Pathways in Vitro , 2022 .