Alimentary Tract| Volume 52, ISSUE 9, P988-994, September 2020

Download started.


Stimulatory effect of gastroesophageal reflux disease (GERD) on pulmonary fibroblast differentiation


      Epidemiological studies indicate that prolonged micro-aspiration of gastric fluid is associated in gastroesophageal reflux disease with the development of chronic respiratory diseases, possibly caused by inflammation-related immunomodulation. Therefore, we sought to ascertain the effect of gastric fluid exposure on pulmonary residential cells. The expression of α-smooth muscle actin as a fibrotic marker was increased in both normal human pulmonary fibroblast cells and mouse macrophages. Gastric fluid enhanced the proliferation and migration of HFL-1 cells and stimulated the expression of inflammatory cytokines in an antibody assay. Elevated expression of the Rho signaling pathway was noted in fibroblast cells stimulated with gastric fluid or conditioned media. These results indicate that gastric fluid alone, or the mixture of proinflammatory mediators induced by gastric fluid in the pulmonary context, can stimulate pulmonary fibroblast cell inflammation, migration, and differentiation, suggesting that a wound healing process is initiated. Subsequent aberrant repair in pulmonary residential cells may lead to pulmonary fibroblast differentiation and fibrotic progression. The results point to a stimulatory effect of chronic GERD on pulmonary fibroblast differentiation, and this may promote the development of chronic pulmonary diseases in the long term.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Digestive and Liver Disease
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Robinson N.B.
        • DiMango E.
        Prevalence of gastroesophageal reflux in cystic fibrosis and implications for lung disease.
        Ann Am Thorac Soc. 2014; 11: 964-968
        • Allaix M.E.
        • Fisichella P.M.
        • Noth I.
        • et al.
        Idiopathic Pulmonary Fibrosis and Gastroesophageal Reflux. Implications for Treatment.
        J Gastrointest Surg. 2014; 18: 100-105
        • Allaix M.E.
        • Fisichella P.M.
        • Noth I.
        • et al.
        The Pulmonary Side of Reflux Disease: from Heartburn to Lung Fibrosis.
        J Gastrointest Surg. 2013; 17: 1526-1535
        • Houghton L.A.
        • Lee A.S.
        • Badri H.
        • et al.
        Respiratory disease and the oesophagus: reflux, reflexes and microaspiration.
        Nat Rev Gastroenterol Hepatol. 2016; 13: 445-460
        • Lee J.S.
        • Ryu J.H.
        • Elicker B.M.
        • et al.
        Gastroesophageal reflux therapy is associated with longer survival in patients with idiopathic pulmonary fibrosis.
        Am J Respir Crit Care Med. 2011; 184: 1390-1394
        • Huang C.C.
        • Chan W.L.
        • Luo J.C.
        • et al.
        Gastroesophageal Reflux Disease and Atrial Fibrillation: a Nationwide Population-Based Study.
        PLoS One. 2012; 7: 5-9
        • Boorsma C.E.
        • Dekkers B.G.J.
        • van Dijk E.M.
        • et al.
        Beyond TGFβ - Novel ways to target airway and parenchymal fibrosis.
        Pulm Pharmacol Ther. 2014; 29: 166-180
        • Alkhouri H.
        • Poppinga W.J.
        • Tania N.P.
        • et al.
        Regulation of pulmonary inflammation by mesenchymal cells.
        Pulm Pharmacol Ther. 2014; 29 (156e165-165)
        • Islami F.
        • Nasseri-Moghaddam S.
        • Pourshams A.
        • et al.
        Determinants of gastroesophageal reflux disease, including hookah smoking and opium use - a cross-sectional analysis of 50,000 individuals.
        PLoS ONE. 2014; 9: e89256
        • Savarino E.
        • Bazzica M.
        • Zentilin P.
        • Pohl D.
        • Parodi A.
        • Cittadini G.
        • Negrini S.
        • Indiveri F.
        • Tutuian R.
        • Savarino V.
        • Ghio M.
        Gastroesophageal reflux and pulmonary fibrosis in scleroderma: a study using pH-impedance monitoring.
        Am J Respir Crit Care Med. 2009; 179: 408-413
        • Savarino E.
        • Carbone R.
        • Marabotto E.
        • Furnari M.
        • Sconfienza L.
        • Ghio M.
        • Zentilin P.
        • Savarino V.
        Gastro-oesophageal reflux and gastric aspiration in idiopathic pulmonary fibrosis patients.
        Eur Respir J. 2013; 42: 1322-1331
        • Chiu H.Y.
        • Chen C.W.
        • Lin H.T.
        • et al.
        Study of gastric fluid induced cytokine and chemokine expression in airway smooth muscle cells and airway remodeling.
        Cytokine. 2011; 56: 726-731
        • Cheng C.M.
        • Hsieh C.C.
        • Lin C.S.
        • et al.
        Macrophage activation by gastric fluid suggests MMP involvement in aspiration-induced lung disease.
        Immunobiology. 2010; 215: 173-181
        • Harowitz J.C.
        • Thannickal V.J.
        Epithelial–Mesenchymal Interactions in Pulmonary Fibrosis.
        Int Rev Cytol. 2010; 14: 384-399
        • Darby I.A.
        Hewitson TD Fibroblast Differentiation in Wound Healing and Fibrosis.
        Int Rev Cytol. 2007; 257: 143-179
        • Fielding C.A.
        • Jones G.W.
        • McLoughlin R.M.
        • McLeod L.
        • Hammond V.J.
        • Uceda J.
        • Williams A.S.
        • Lambie M.
        • Foster T.L.
        • Liao C.T.
        • Rice C.M.
        • Greenhill C.J.
        • Colmont C.S.
        • Hams E.
        • Coles B.
        • Kift-Morgan A.
        • Newton Z.
        • Craig K.J.
        • Williams J.D.
        • Williams G.T.
        • Davies S.J.
        • Humphreys I.R.
        • O'Donnell V.B.
        • Taylor P.R.
        • Jenkins B.J.
        • Topley N.
        • Jones S.A.
        Interleukin-6 signaling drives fibrosis in unresolved inflammation.
        Immunity. 2014; 40: 40-50
        • Hinz B.
        • Celetta G.
        • Tomasek J.J.
        • Gabbiani G.
        • Chaponnier C.
        Alpha-smooth muscle actin expression upregulates fibroblast contractile activity.
        Mol Biol Cell. 2001; 12: 2730-2741
        • Small E.M.
        The actin-MRTF-SRF gene regulatory axis and myofibroblast differentiation.
        J Cardiovasc Transl Res. 2012; 5: 794-804
        • Camelo A.
        • Dunmore R.
        • Sleeman M.A.
        • et al.
        The epithelium in idiopathic pulmonary fibrosis: breaking the barrier.
        Front Pharmacol. 2014; 4: 173-192
        • Miftahussurur M.
        • Doohan D.
        • Nusi I.A.
        • et al.
        Gastroesophageal reflux disease in an area with low Helicobacter pylori infection prevalence.
        PLoS ONE. 2018; 13e0205644
        • Serbina N V.
        • Jia T.
        • Hohl T.M.
        • et al.
        Monocyte-Mediated Defense Against Microbial Pathogens.
        Annu Rev Immunol. 2008; 26: 421-452
        • Gallucci R.M.
        • Lee E.G.
        • Tomasek J.J
        IL-6 modulates alpha-smooth muscle actin expression in dermal fibroblasts from IL-6-deficient mice.
        J Invest Dermatol. 2006; 126: 561-568
        • Zhou Y.
        • Huang X.
        • Hecker L.
        • et al.
        Inhibition of mechanosensitive signaling in myofibroblasts ameliorates experimental pulmonary fibrosis.
        J Clin Invest. 2013; 123: 1096-1108
        • Holmström F.
        • Shimizu S.
        • Shimizu T.
        • et al.
        Protective effect of hydroxyfasudil, a Rho kinase inhibitor, on ventral prostatic hyperplasia in the spontaneously hypertensive rat.
        Prostate. 2015; 75: 1774-1782
        • Crosby L.M.
        • Waters C.M.
        Epithelial repair mechanisms in the lung.
        Am J Physiol - Lung Cell Mol Physiol. 2010; 298: L715-L731
        • Scotton C.J.
        • Chambers R.C.
        Molecular targets in pulmonary fibrosis: the myofibroblast in focus.
        Chest. 2007; 132: 1311-1321
        • Moffitt K.L.
        • Martin S.L.
        • Jones A.M.
        • et al.
        Inflammatory and immunological biomarkers are not related to survival in adults with cystic fibrosis.
        J Cyst Fibros. 2014; 13: 63-68
        • Atabai K.
        • Ishigaki M.
        • Geiser T.
        • Ueki I.
        • et al.
        Keratinocyte growth factor can enhance alveolar epithelial repair by nonmitogenic mechanisms.
        Am J Physiol - Lung Cell Mol Physiol. 2002; 283: 163-169
        • Borrelli O.
        • Battaglia M.
        • Galos F.
        • et al.
        Non-acid gastro-oesophageal reflux in children with suspected pulmonart aspiration.
        Dig Liver Dis. 2010; 42: 115-121
        • Yamada T.
        • Ishida Y.
        • Nakamura Y.
        • et al.
        Bile-acid-induced calcium signaling in mouse esophageal epithelial cells.
        Biochem Biophys Res Commun. 2011; 414: 789-794
        • Williamson D.J.
        • Begley C.G.
        • Vadas M.A.
        • et al.
        The detection and initial characterization of colony-stimulating factors in synovial fluid.
        Clin Exp Immunol. 1988; 72: 67-73
        • Ushach I.
        • Zlotnik A.
        Biological role of granulocyte macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) on cells of the myeloid lineage.
        J Leukoc Biol. 2016; 100: 481-489
        • Cook A.D.
        • Pobjoy J.
        • Steidl S.
        • et al.
        Granulocyte-macrophage colony-stimulating factor is a key mediator in experimental osteoarthritis pain and disease development.
        Arthritis Res Ther. 2012; 14: 1-9
        • Shiomi A.
        • Usui T.
        • Ishikawa Y.
        • et al.
        GM-CSF but Not IL-17 Is Critical for the Development of Severe Interstitial Lung Disease in SKG Mice.
        J Immunol. 2014; 193: 849-859
        • Vlahos R.
        • Bozinovski S.
        • Hamilton J.A.
        • et al.
        Therapeutic potential of treating chronic obstructive pulmonary disease (COPD) by neutralising granulocyte macrophage-colony stimulating factor (GM-CSF).
        Pharmacol Ther. 2006; 112: 106-115
        • Orlacchio A.
        • Bernardi G.
        • Orlacchio A.
        • et al.
        Stem cells and neurological diseases.
        Discov Med. 2010; 9: 546-553
        • Forechi L.
        • Baldo M.P.
        • Meyerfreund D.
        • et al.
        Granulocyte colony-stimulating factor improves early remodeling in isoproterenol-induced cardiac injury in rats.
        Pharmacol Reports. 2012; 64: 643-649
        • Kohan M.
        • Puxeddu I.
        • Reich R.
        • et al.
        Eotaxin-2/CCL24 and eotaxin-3/CCL26 exert differential profibrogenic effects on human lung fibroblasts. Ann Allergy.
        Asthma Immunol. 2010; 104: 66-72
        • Guiot J.
        • Bondue B.
        • Henket M.
        • et al.
        Raised serum levels of IGFBP-1 and IGFBP-2 in idiopathic pulmonary fibrosis.
        BMC Pulm Med. 2016; 16: 1-7
        • Yanaba K.
        • Komura K.
        • Kodera M.
        • et al.
        Serum levels of monocyte chemotactic protein-3/CCL7 are raised in patients with systemic sclerosis: association with extent of skin sclerosis and severity of pulmonary fibrosis.
        Ann Rheum Dis. 2006; 65: 124-126
        • Lesina M.
        • Wörmann S.M.
        • Neuhöfer P.
        • et al.
        Interleukin-6 in inflammatory and malignant diseases of the pancreas.
        Semin Immunol. 2014; 26: 80-87
        • Saiki P.
        • Nakajima Y.
        • Van Griensven L.
        • et al.
        Real-time monitoring of IL-6 and IL-10 reporter expression for anti-inflammation activity in live RAW 264.7 cells.
        Biochem Biophys Res Commun. 2018; 505: 885-890
        • Mital J.
        • Meissner M.
        • Soldati D.
        • et al.
        Conditional Expression of.
        Mol Biol Cell. 2005; 16: 4341-4349
        • Kobayashi T.
        • Tanaka K.
        • Fujita T.
        • et al.
        Bidirectional role of IL-6 signal in pathogenesis of lung fibrosis.
        Respir Res. 2015; 16: 1-14
        • Ancey C.
        • Corbi P.
        • Froger J.
        • et al.
        Secretion of IL-6, IL-11 and LIF by human cardiomyocytes in primary culture.
        Cytokine. 2002; 18: 199-205
        • Shima Y.
        • Kuwahara Y.
        • Murota H.
        The skin of patients with systemic sclerosis softened during the treatment with anti-IL-6 receptor antibody tocilizumab.
        Rheumatology. 2010; 49: 2408-2412
        • El Kasmi K.C.
        • Pugliese S.C.
        • Riddle S.R.
        • et al.
        Adventitial Fibroblasts Induce a Distinct Proinflammatory/Profibrotic Macrophage Phenotype in Pulmonary Hypertension.
        J Immunol. 2014; 193: 597-609
        • Ayaub E.A.
        • Dubey A.
        • Imani J.
        • et al.
        Overexpression of OSM and IL-6 impacts the polarization of pro-fibrotic macrophages and the development of bleomycin-induced lung fibrosis.
        Sci Rep. 2017; 7: 1-16
        • Ma F.
        • Li Y.
        • Jia L.
        • et al.
        Macrophage-stimulated cardiac fibroblast production of IL-6 is essential for TGF β/Smad activation and cardiac fibrosis induced by angiotensin II.
        PLoS ONE. 2012; 7: 1-9
        • Duecker R.
        • Baer P.
        • Eickmeier O.
        • et al.
        Oxidative stress-driven pulmonary inflammation and fibrosis in a mouse model of human ataxia-telangiectasia.
        Redox Biol. 2018; 14: 645-655

      Linked Article

      • A further step forward in our knowledge of the pathogenetic role of gastroesophageal reflux in pulmonary fibrosis
        Digestive and Liver DiseaseVol. 52Issue 9
        • Preview
          Pulmonary fibrosis is a repair response in lung tissue injury that involves loss of epithelial cells and accumulation of fibroblasts/myofibroblasts [1]. The main triggers of this fibrotic progression might be viral infections, organic and inorganic dusts, smoking and Gastroesophageal Reflux Disease (GERD). Furthermore, the majority of published studies have suggested that there is a strong comorbidity between GERD and Idiopathic pulmonary fibrosis (IPF) [2,3]. Based on this knowledge, we have read with interest the paper entitled “Stimulatory Effect of Gastroesophageal Reflux Disease (GERD) on Pulmonary Fibroblast Differentiation” written by Cheng et al [4].
        • Full-Text
        • PDF