Role of Nasal Fibroblasts in Airway Remodeling of Chronic Rhinosinusitis: The Modulating Functions Reexamined

Chronic rhinosinusitis (CRS) is a multifactorial inflammatory disease of the nose and sinuses that affects more than 10% of the adult population worldwide. Currently, CRS is classified into endotypes according to the inflammatory response (Th1, Th2, and Th17) or the distribution of immune cells in the mucosa (eosinophilic and non-eosinophilic). CRS induces mucosal tissue remodeling. Extracellular matrix (ECM) accumulation, fibrin deposition, edema, immune cell infiltration, and angiogenesis are observed in the stromal region. Conversely, epithelial-to-mesenchymal transition (EMT), goblet cell hyperplasia, and increased epithelial permeability, hyperplasia, and metaplasia are found in the epithelium. Fibroblasts synthesize collagen and ECM, which create a structural skeleton of tissue and play an important role in the wound-healing process. This review discusses recent knowledge regarding the modulation of tissue remodeling by nasal fibroblasts in CRS.

[1]  Shiyao Zhang,et al.  M2 macrophage-related gene signature in chronic rhinosinusitis with nasal polyps , 2022, Frontiers in Immunology.

[2]  M. Szczepański,et al.  Immunological Aspects of Chronic Rhinosinusitis , 2022, Diagnostics.

[3]  Hongtian Wang,et al.  The Role of Epithelial-Mesenchymal Transition in Chronic Rhinosinusitis , 2022, International Archives of Allergy and Immunology.

[4]  J. Girard,et al.  Interleukin-33 (IL-33): A critical review of its biology and the mechanisms involved in its release as a potent extracellular cytokine. , 2022, Cytokine.

[5]  Dae Woo Kim,et al.  Eosinophil-Derived Osteopontin Induces the Expression of Pro-Inflammatory Mediators and Stimulates Extracellular Matrix Production in Nasal Fibroblasts: The Role of Osteopontin in Eosinophilic Chronic Rhinosinusitis , 2022, Frontiers in Immunology.

[6]  A. Kato,et al.  Mechanisms and pathogenesis of chronic rhinosinusitis. , 2022, The Journal of allergy and clinical immunology.

[7]  Gang Yin,et al.  Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities , 2022, Signal Transduction and Targeted Therapy.

[8]  X. Dufour,et al.  Cytokine Signature and Involvement in Chronic Rhinosinusitis with Nasal Polyps , 2021, International journal of molecular sciences.

[9]  Sung-Woo Cho,et al.  Lessons From Localized Chronic Rhinosinusitis With Nasal Polyps , 2021, Allergy, asthma & immunology research.

[10]  Keigo Nakamura,et al.  Nasal polyp fibroblasts (NPFs)-derived exosomes are important for the release of vascular endothelial growth factor from cocultured eosinophils and NPFs. , 2021, Auris, nasus, larynx.

[11]  Kevin Wei,et al.  Fibroblast pathology in inflammatory diseases. , 2021, The Journal of clinical investigation.

[12]  Kyle T. Mincham,et al.  Our evolving view of neutrophils in defining the pathology of chronic lung disease , 2021, Immunology.

[13]  Minghua Wu,et al.  Pattern recognition receptors in health and diseases , 2021, Signal Transduction and Targeted Therapy.

[14]  N. Rosenthal,et al.  Fibroblasts: Origins, definitions, and functions in health and disease , 2021, Cell.

[15]  Hongmei Zhou,et al.  Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer , 2021, Signal Transduction and Targeted Therapy.

[16]  P. Dong,et al.  Salvianolic acid B inhibits myofibroblast differentiation and extracellular matrix accumulation in nasal polyp fibroblasts via the TGF-β1 signaling pathway. , 2021, Molecular Medicine Reports.

[17]  Jingyi Yang,et al.  Mucosal epithelial cells: the initial sentinels and responders controlling and regulating immune responses to viral infections , 2021, Cellular & Molecular Immunology.

[18]  G. Kollias,et al.  Fibroblasts as immune regulators in infection, inflammation and cancer , 2021, Nature Reviews Immunology.

[19]  Yuan-yuan Liu,et al.  Extracellular matrix: an important regulator of cell functions and skeletal muscle development , 2021, Cell & Bioscience.

[20]  Chunye Zhang,et al.  Function of Macrophages in Disease: Current Understanding on Molecular Mechanisms , 2021, Frontiers in Immunology.

[21]  Tae Hoon Kim,et al.  Advances in the Knowledge of the Underlying Airway Remodeling Mechanisms in Chronic Rhinosinusitis Based on the Endotypes: A Review , 2021, International journal of molecular sciences.

[22]  C. Bachert,et al.  Involvement of the extracellular matrix proteins periostin and tenascin C in nasal polyp remodeling by regulating the expression of MMPs , 2020, Clinical and translational allergy.

[23]  Kristine A. Smith,et al.  International consensus statement on allergy and rhinology: rhinosinusitis 2021 , 2020, International forum of allergy & rhinology.

[24]  D. Ribatti,et al.  Epithelial-Mesenchymal Transition in Cancer: A Historical Overview , 2020, Translational oncology.

[25]  K. Anderson,et al.  The Epithelial-to-Mesenchymal Transition (EMT) in Development and Cancer. , 2020, Annual review of cancer biology.

[26]  W. Fokkens EPOS2020: a major step forward. , 2020, Rhinology.

[27]  Raj Kumar,et al.  A panoramic review of IL-6: Structure, pathophysiological roles and inhibitors. , 2020, Bioorganic & medicinal chemistry.

[28]  Ju-Hyung Kang,et al.  Lipopolysaccharide regulates thymic stromal lymphopoietin expression via TLR4/MAPK/Akt/NF‐κB‒signaling pathways in nasal fibroblasts: differential inhibitory effects of macrolide and corticosteroid , 2020, International forum of allergy & rhinology.

[29]  Jegadevswari Selvarajah,et al.  Current and Alternative Therapies for Nasal Mucosa Injury: A Review , 2020, International journal of molecular sciences.

[30]  Heung-Man Lee,et al.  Cigarette smoke extract inhibits cell migration and contraction via the reactive oxygen species/adenosine monophosphate–activated protein kinase pathway in nasal fibroblasts , 2019, International forum of allergy & rhinology.

[31]  Heung-Man Lee,et al.  TGF-β1-induced HSP47 regulates extracellular matrix accumulation via Smad2/3 signaling pathways in nasal fibroblasts , 2019, Scientific Reports.

[32]  K. McLaughlin,et al.  Mechanisms of physiological tissue remodeling in animals: Manipulating tissue, organ, and organism morphology. , 2019, Developmental biology.

[33]  W. Fokkens,et al.  Prevalence of chronic rhinosinusitis in the general population based on sinus radiology and symptomatology , 2019, The Journal of allergy and clinical immunology.

[34]  Hyun-Woo Shin,et al.  The IFN-γ–p38, ERK kinase axis exacerbates neutrophilic chronic rhinosinusitis by inducing the epithelial-to-mesenchymal transition , 2019, Mucosal Immunology.

[35]  Y. Kakeji,et al.  Fibroblast activation protein-positive fibroblasts promote tumor progression through secretion of CCL2 and interleukin-6 in esophageal squamous cell carcinoma , 2019, Laboratory Investigation.

[36]  Hyun-Woo Shin,et al.  The IFN-γ – p 38 , ERK kinase axis exacerbates neutrophilic chronic rhinosinusitis by inducing the epithelial-to-mesenchymal transition , 2019 .

[37]  A. Lane,et al.  Nasal polyp fibroblasts modulate epithelial characteristics via Wnt signaling , 2018, International forum of allergy & rhinology.

[38]  Jong Seong Roh,et al.  Damage-Associated Molecular Patterns in Inflammatory Diseases , 2018, Immune network.

[39]  Liang Dong,et al.  TSLP promotes asthmatic airway remodeling via p38-STAT3 signaling pathway in human lung fibroblast , 2018, Experimental lung research.

[40]  D. Parrino,et al.  Nasal polyposis pathophysiology: Endotype and phenotype open issues. , 2018, American journal of otolaryngology.

[41]  K. Samitas,et al.  Upper and lower airway remodelling mechanisms in asthma, allergic rhinitis and chronic rhinosinusitis: The one airway concept revisited , 2018, Allergy.

[42]  T. Wynn,et al.  Type 2 immunity in tissue repair and fibrosis , 2017, Nature Reviews Immunology.

[43]  R. Warrington,et al.  An introduction to immunology and immunopathology , 2011, Allergy, Asthma & Clinical Immunology.

[44]  L. Boulet Airway remodeling in asthma: update on mechanisms and therapeutic approaches , 2018, Current opinion in pulmonary medicine.

[45]  K. Shaari,et al.  Blockade of Eosinophil-Induced Bronchial Epithelial-Mesenchymal Transition with a Geranyl Acetophenone in a Coculture Model , 2017, Front. Pharmacol..

[46]  Heung-Man Lee,et al.  Vitamin D attenuates myofibroblast differentiation and extracellular matrix accumulation in nasal polyp-derived fibroblasts through smad2/3 signaling pathway , 2017, Scientific Reports.

[47]  Yong-Min Kim,et al.  IL-25-induced activation of nasal fibroblast and its association with the remodeling of chronic rhinosinusitis with nasal polyposis , 2017, PloS one.

[48]  Shao-Cong Sun,et al.  NF-κB signaling in inflammation , 2017, Signal Transduction and Targeted Therapy.

[49]  Jeong-Whun Kim,et al.  Classification of chronic rhinosinusitis according to a nasal polyp and tissue eosinophilia: limitation of current classification system for Asian population , 2017, Asia Pacific allergy.

[50]  A. Peters,et al.  Neutrophils are a major source of the epithelial barrier disrupting cytokine oncostatin M in patients with mucosal airways disease , 2017, The Journal of allergy and clinical immunology.

[51]  J. Axelrod,et al.  Wnt Signaling in Chronic Rhinosinusitis with Nasal Polyps , 2017, American journal of respiratory cell and molecular biology.

[52]  Kevin Wei,et al.  Autocrine Loop Involving IL‐6 Family Member LIF, LIF Receptor, and STAT4 Drives Sustained Fibroblast Production of Inflammatory Mediators , 2017, Immunity.

[53]  Zhenggang Zhu,et al.  IL-6 secreted by cancer-associated fibroblasts promotes epithelial-mesenchymal transition and metastasis of gastric cancer via JAK2/STAT3 signaling pathway , 2017, Oncotarget.

[54]  Gary L. Bowlin,et al.  An overview of the role of neutrophils in innate immunity, inflammation and host-biomaterial integration , 2017, Regenerative biomaterials.

[55]  R. Schleimer Immunopathogenesis of Chronic Rhinosinusitis and Nasal Polyposis. , 2017, Annual review of pathology.

[56]  C. Bachert,et al.  Diversity of TH cytokine profiles in patients with chronic rhinosinusitis: A multicenter study in Europe, Asia, and Oceania. , 2016, The Journal of allergy and clinical immunology.

[57]  Heung-Man Lee,et al.  Effect of Doxycycline on Transforming Growth Factor-Beta-1–Induced Matrix Metalloproteinase 2 Expression, Migration, and Collagen Contraction in Nasal Polyp–Derived Fibroblasts , 2016, American Journal of Rhinology & Allergy.

[58]  T. Wynn,et al.  Macrophages in Tissue Repair, Regeneration, and Fibrosis. , 2016, Immunity.

[59]  J. Wilson,et al.  The Role of the Fibroblast in Inflammatory Upper Airway Conditions. , 2016, The American journal of pathology.

[60]  Heung-Man Lee,et al.  Stimulatory effects of histamine on migration of nasal fibroblasts , 2015, International forum of allergy & rhinology.

[61]  R. Schleimer,et al.  Chronic Rhinosinusitis and the Coagulation System , 2015, Allergy, asthma & immunology research.

[62]  M. Rothenberg,et al.  Eosinophils in mucosal immune responses , 2015, Mucosal Immunology.

[63]  S. Jimenez,et al.  The significance of macrophage polarization subtypes for animal models of tissue fibrosis and human fibrotic diseases , 2015, Clinical and Translational Medicine.

[64]  V. Thannickal,et al.  Plasminogen activator inhibitor 1, fibroblast apoptosis resistance, and aging-related susceptibility to lung fibrosis , 2015, Experimental Gerontology.

[65]  K. Ikeda,et al.  Comparative analysis of cytokine release from epithelial cell cultures of the upper airway. , 2015, Rhinology.

[66]  Ju-Hyung Kang,et al.  Lipopolysaccharide Induces Pro-Inflammatory Cytokines and MMP Production via TLR4 in Nasal Polyp-Derived Fibroblast and Organ Culture , 2014, PloS one.

[67]  T. Wilgus,et al.  Vascular Endothelial Growth Factor and Angiogenesis in the Regulation of Cutaneous Wound Repair. , 2014, Advances in wound care.

[68]  Toshio Tanaka,et al.  IL-6 in inflammation, immunity, and disease. , 2014, Cold Spring Harbor perspectives in biology.

[69]  Heung-Man Lee,et al.  Inhibitory Effect of Prostaglandin E2 on the Migration of Nasal Fibroblasts , 2014 .

[70]  Ju-Hyung Kang,et al.  Steroids inhibit vascular endothelial growth factor expression via TLR4/Akt/NF-κB pathway in chronic rhinosinusitis with nasal polyp , 2014, Experimental biology and medicine.

[71]  Heung-Man Lee,et al.  Inhibitory Effect of Prostaglandin E2 on the Migration of Nasal Fibroblasts , 2014, American journal of rhinology & allergy.

[72]  C. Tschöpe,et al.  Crosstalk between fibroblasts and inflammatory cells. , 2014, Cardiovascular research.

[73]  L. Ivashkiv,et al.  Regulation of type I interferon responses , 2013, Nature Reviews Immunology.

[74]  F. Liu,et al.  The Development of Nasal Polyp Disease Involves Early Nasal Mucosal Inflammation and Remodelling , 2013, PloS one.

[75]  P. Bainbridge,et al.  Wound healing and the role of fibroblasts. , 2013, Journal of wound care.

[76]  D. Eom,et al.  Expression of matrix metalloproteinase 2 and 9 and tissue inhibitor of metalloproteinase 1 in nonrecurrent vs recurrent nasal polyps. , 2013, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.

[77]  A. Peters,et al.  Increased expression of factor XIII-A in patients with chronic rhinosinusitis with nasal polyps. , 2013, The Journal of allergy and clinical immunology.

[78]  Ji-Young Um,et al.  Activation of TLR4 induces VEGF expression via Akt pathway in nasal polyps , 2013, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[79]  Takahiro Matsumoto,et al.  Eosinophils Promote Epithelial to Mesenchymal Transition of Bronchial Epithelial Cells , 2013, PloS one.

[80]  A. Peters,et al.  Excessive fibrin deposition in nasal polyps caused by fibrinolytic impairment through reduction of tissue plasminogen activator expression. , 2013, American journal of respiratory and critical care medicine.

[81]  J. Silva,et al.  Matrix metalloproteinases and their impact on sinusal extension in chronic rhinosinusitis with nasal polyps , 2013, European Archives of Oto-Rhino-Laryngology.

[82]  T. Himi,et al.  Regulation of interleukin‐33 and thymic stromal lymphopoietin in human nasal fibroblasts by proinflammatory cytokines , 2012, The Laryngoscope.

[83]  N. Otori,et al.  Identification of Chronic Rhinosinusitis Phenotypes Using Cluster Analysis , 2012, American journal of rhinology & allergy.

[84]  B. Rubin,et al.  IL‐13‐induced MUC5AC production and goblet cell differentiation is steroid resistant in human airway cells , 2011, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[85]  M. Shibuya Vascular Endothelial Growth Factor (VEGF) and Its Receptor (VEGFR) Signaling in Angiogenesis: A Crucial Target for Anti- and Pro-Angiogenic Therapies. , 2011, Genes & cancer.

[86]  J. Wang,et al.  Fibroblasts and myofibroblasts in wound healing: force generation and measurement. , 2011, Journal of tissue viability.

[87]  S. Cayli,et al.  Distribution of matrix metalloproteinases MMP-1, MMP-2, MMP-8 and tissue inhibitor of matrix metalloproteinases-2 in nasal polyposis and chronic rhinosinusitis. , 2011, Histology and histopathology.

[88]  C. Bachert,et al.  Tissue remodeling in chronic rhinosinusitis , 2011, Current opinion in allergy and clinical immunology.

[89]  C. Bachert,et al.  Expression of TGF, matrix metalloproteinases, and tissue inhibitors in Chinese chronic rhinosinusitis. , 2010, The Journal of allergy and clinical immunology.

[90]  Takwi Nkyimbeng,et al.  Altered lymphocyte trafficking and diminished airway reactivity in transgenic mice expressing human MMP-9 in a mouse model of asthma. , 2010, American journal of physiology. Lung cellular and molecular physiology.

[91]  J. Shute,et al.  Coagulation factors in the airways in moderate and severe asthma and the effect of inhaled steroids , 2009, Thorax.

[92]  Raghu Kalluri,et al.  The basics of epithelial-mesenchymal transition. , 2009, The Journal of clinical investigation.

[93]  H. Ustun,et al.  The expression of MMP-2, MMP-7, MMP-9, and TIMP-1 in chronic rhinosinusitis and nasal polyposis , 2008, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[94]  R. Pawankar,et al.  Heterogeneous response of nasal and lung fibroblasts to transforming growth factor‐β1 , 2008, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[95]  Craig E. Higgins,et al.  TGF-beta1-induced plasminogen activator inhibitor-1 expression in vascular smooth muscle cells requires pp60(c-src)/EGFR(Y845) and Rho/ROCK signaling. , 2008, Journal of molecular and cellular cardiology.

[96]  Atsushi Kato,et al.  Epithelium: at the interface of innate and adaptive immune responses. , 2007, The Journal of allergy and clinical immunology.

[97]  E. Toskala,et al.  Metalloproteinase Function in Chronic Rhinosinusitis With Nasal Polyposis , 2007, The Laryngoscope.

[98]  R. Pawankar,et al.  Expression of MCP-4 by TLR ligand-stimulated nasal polyp fibroblasts , 2007, Acta oto-laryngologica.

[99]  C. Bachert,et al.  Differentiation of chronic sinus diseases by measurement of inflammatory mediators , 2006, Allergy.

[100]  D. Cines,et al.  LRP and αvβ3 mediate tPA activation of smooth muscle cells , 2006 .

[101]  D. Hebenstreit,et al.  IL‐4 induces expression of TARC/CCL17 via two STAT6 binding sites , 2006, European journal of immunology.

[102]  Ze-qing Li,et al.  [Effect of myofibroblast accumulation on the formation and development of nasal polyps]. , 2006, Zhonghua er bi yan hou tou jing wai ke za zhi = Chinese journal of otorhinolaryngology head and neck surgery.

[103]  M. Kowalski,et al.  Pathogenesis of nasal polyps: An update , 2005, Current allergy and asthma reports.

[104]  Toshiyuki Shimizu,et al.  Suppression of Matrix Metalloproteinase Production in Nasal Fibroblasts by Tranilast, an Antiallergic Agent, In Vitro , 2005, Mediators of inflammation.

[105]  K. Asano,et al.  Influence of fluticasone propionate on the production of vascular endothelial growth factor and basic fibroblast growth factor from nasal fibroblasts in vitro. , 2004, In vivo.

[106]  S. Madoiwa,et al.  Expression profiles of fibrinolytic components in nasal mucosa , 2004, Histochemistry and Cell Biology.

[107]  R. Visse,et al.  This Review Is Part of a Thematic Series on Matrix Metalloproteinases, Which Includes the following Articles: Matrix Metalloproteinase Inhibition after Myocardial Infarction: a New Approach to Prevent Heart Failure? Matrix Metalloproteinases in Vascular Remodeling and Atherogenesis: the Good, the Ba , 2022 .

[108]  M. Kondo,et al.  Interleukin-13 induces goblet cell differentiation in primary cell culture from Guinea pig tracheal epithelium. , 2002, American journal of respiratory cell and molecular biology.

[109]  C. Halloran,et al.  Pathophysiology of Wound Healing , 2002 .

[110]  R. Homer,et al.  Cytokine regulation of mucus production in a model of allergic asthma. , 2002, Novartis Foundation symposium.

[111]  Chun Kim,et al.  Effects of Dexamethasone on RANTES Expression of Nasal Fibroblast , 2001 .

[112]  R. Pawankar,et al.  Expression of RANTES by IL-1 β and TNF-α stimulated nasal polyp fibroblasts , 2000 .

[113]  R. Homer,et al.  Induction of Airway Mucus Production By T Helper 2 (Th2) Cells: A Critical Role For Interleukin 4 In Cell Recruitment But Not Mucus Production , 1997, The Journal of experimental medicine.