Therapeutic implication of genetic variants of IL13 and STAT4 in airway remodelling with bronchial asthma

Abstract

SummaryBackground Several gene variants identified in bronchial asthmatic patients are associated with a decrease in pulmonary function. The effects of this intervention on pulmonary function have not been fully researched. Objective We determined the effects of high-dose inhaled corticosteroids (ICSs) on decreased pulmonary function in asthmatic Japanese patients with variants of IL13 and STAT4 during long-term treatments with low to mild doses of ICS. Methods In this study, 411 patients with bronchial asthma who were receiving ICSs and living in Japan were recruited, were genotyped, and underwent pulmonary function tests and fibreoptic examinations. The effects of 2 years of high-dose ICSs administered to asthmatic patients who were homozygous for IL13 AA of rs20541 or STAT4 TT of rs925847 and who progressed to airway remodelling were investigated. Results High-dose ICS treatment increased the pulmonary function of patients homozygous for IL13 AA of rs20541 but not of patients homozygous for STAT4 TT of rs925847. The increased concentrations of the mediators IL23, IL11, GMCSF, hyaluronic acid, IL24, and CCL8 in bronchial lavage fluid (BLF) were diminished after high-dose ICS treatment in patients homozygous for IL13 AA of rs20541. Conclusion and Clinical Relevance IL13 AA of rs20541 and STAT4 TT of rs925847 are potential genomic biomarkers for predicting lower pulmonary function. The administration of high-dose ICSs to asthmatic patients with genetic variants of IL13 AA may inhibit the advancement of airway remodelling. The genetic variants of STAT4 TT did not respond to high-dose ICSs. Therefore, using medications other than ICSs must be considered even during the initial treatment of bronchial asthma. These genetic variants may aid in the realization of personalized and phenotype-specific therapies for bronchial asthma.

Low‐molecular‐mass hyaluronan induces pulmonary inflammation by up‐regulation of Mcl‐1 to inhibit neutrophil apoptosis via PI3K/Akt1 pathway

“…Low‐molecular‐mass HA (LMMHA), a product of rapid turnover and degradation of HA, can serve as an intracellular signalling molecule in inflammation and has been found to be pro‐inflammatory . LMMHA is dramatically increased in patients with idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma and acute respiratory distress syndrome . A previous study on the role of LMMHA in lung injury revealed that blocking the effect of LMMHA with specific peptides decreases neutrophil infiltration and fibrosis activity and alleviates lung tissue damage in a bleomycin‐mediated LMMHA‐induced mouse lung injury model .…”

“…3 LMMHA is dramatically increased in patients with idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma and acute respiratory distress Abbreviations: BALF, bronchoalveolar lavage fluid; ECM, extracellular matrix; ERK 1/2, extracellular signal-regulated kinase 1/2; IFN-b, interferon-b; IL-1b, interleukin-1b; IRF-3, interferon regulatory factor 3; KC, keratinocyte cell-derived chemokine; LMMHA, low-molecular-mass hyaluronan; Mcl-1, myeloid leukaemia cell differentiation protein; MMP-9, matrix metalloproteinase-9; MPO, myeloperoxidase; PBS, phosphate-buffered saline; PI3K, phosphoinositide 3-kinase; TLR, Toll-like receptor; WT, wild-type ª 2018 John Wiley & Sons Ltd, Immunology, 155, 387-395 syndrome. [4][5][6][7] A previous study on the role of LMMHA in lung injury revealed that blocking the effect of LMMHA with specific peptides decreases neutrophil infiltration and fibrosis activity and alleviates lung tissue damage in a bleomycin-mediated LMMHA-induced mouse lung injury model. 8 These studies establish the importance of LMMHA in respiratory disorders and encourage further study of the pro-inflammatory properties of LMMHA.…”

Self-Reported Allergic Rhinitis and/or Allergic Conjunctivitis Associate with <b><i>IL13</i></b> rs20541 Polymorphism in Finnish Adult Asthma Patients

“…Another study failed to find statistical significance between rs20541 polymorphism and treatment and symptom severity of asthma [14]. Another group also reports an association between the IL13 AA rs20541 genotype and airway remodeling in Japanese asthmatics [15]. …”

Impact of the genetic variants of GLCCI1 on clinical features of asthmatic patients

“…9 In northern European populations of asthmatic children and young adults, GLCCI1 genotype rs37972 has been demonstrated to not be associated with an ICS efficacy decrease in lung function and asthma symptom scores. 11,12 Thus, increased FEV1 or recovered airway remodeling were dependent on the genetic background and treatment content. Administration of high-dose ICS to asthmatic patients with genetic variants of STAT4 did not respond to it, whereas the genetic variants of IL13 AA might avoid the advancing of airway remodeling.…”

“…Administration of high-dose ICS to asthmatic patients with genetic variants of STAT4 did not respond to it, whereas the genetic variants of IL13 AA might avoid the advancing of airway remodeling. 11,12 Thus, increased FEV1 or recovered airway remodeling were dependent on the genetic background and treatment content. In the current study, we aimed to assess whether variants in the GLCCI1 rs37972 and rs37973 genotypes were associated with relationships between lung function and treatment in Japanese adults receiving ICS treatment, and to identify GLCCI1 positive cells in the bronchial airways.…”