ORMDL3 is associated with airway remodeling in asthma via the ERK/MMP-9 pathway

Abstract

ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) has been previously implicated in asthma pathogenesis, its effect on airway remodeling remains to be elucidated. The present study examined the expression levels of ORMDL3 in a mouse model of asthma. Mice were divided into three groups: Asthmatic model (n=10), budesonide-treated (n=10) and a control group (n=8). Asthma was induced by sensitization with ovalbumin (OVA) and aluminum hydroxide on day 1, 7 and 14. Subsequently mice were exposed to OVA three times per week from day 28. In order to investigate the mechanism of airway remodeling 100 µg/kg aerosol budesonide was administered to 6 animals prior to exposure to OVA. The condition of lung tissues was assessed through histology, and the expression levels of ORMDL3, phosphorylated-extracellular-signal regulated kinase (p-ERK) and matrix metallopeptidase-9 (MMP-9) were quantified using immunohistochemistry, reverse transcription-quantitative polymerase chain reaction and western blotting. A severe inflammatory response and airway remodeling were pretreatment with budesonide. Expression levels of ORMDL3, phosphorylated (p)-ERK and MMP-9 were significantly greater in the asthma-model group; however, in the group pretreated with budesonide their expression was reduced. Expression levels of ORMDL3, p-ERK and MMP-9 were significantly positively correlated with bronchial wall thickness. ORMDL3 expression was significantly positively correlated with p-ERK and MMP-9. Therefore, increased ORMDL3 expression may induce the p-ERK/MMP-9 pathway to promote pathological airway remodeling in patients with asthma.

ORMDL3 may participate in the pathogenesis of bronchial epithelial‑mesenchymal transition in asthmatic mice with airway remodeling

“…ORMDL3 might aggravate asthmatic airway remodeling by causing bronchial epithelial EMT, a novel aspect of the mechanism of ORMDL3 in asthma. Yu et al (19) have also reported ORMDL3 was associated with airway remodeling in asthma via the ERK/MMP-9 pathway. Our study had some similarity to Yu et al (19) about the methods, the purpose and the results.…”

“…Yu et al (19) have also reported ORMDL3 was associated with airway remodeling in asthma via the ERK/MMP-9 pathway. Our study had some similarity to Yu et al (19) about the methods, the purpose and the results. Two papers both investigated the mechanism of ORMDL3 in airway remodeling in asthma.…”

“…Thus, budesonide treatment is more likely to directly inhibit p-ERK/MMP-9, leading to reduction in airway remodeling, rather than the reduced expression of ORMDL3 affect the p-ERK/MMP-9 pathway resulted in reduction in airway remodeling. There was lack of evidence to prove the relationship between ORMDL3, p-ERK/MMP-9 pathway and airway remodeling in Yu et al's paper (19). Airway remodeling in asthma includes smooth muscle cell proliferation and hypertrophy, extracellular matrix deposition, basement membrane thickening, inflammatory cell infiltration and gland proliferation, hypertrophy and epithelial-mesenchymal transition.…”

“…Yu et al (19) focuses on the study of the relationship between ORMDL3 and ERK/MMP-9 channels, while our paper focuses on the study of the relationship between ORMDL3 and EMT. But Yu et al (19) did not explain the direct relationship between the ORMDL3 and the p-ERK/MMP-9 pathway in vivo, nor did it indicate whether ORMDL3 regulates p-ERK/MMP-9 or p-ERK/MMP-9 regulates ORMDL3. Otherwise, it is known that Inhaled corticosteroids is the first choice to treat asthma.…”

ORMDL3 and its implication in inflammatory disorders

“…Airway remodeling centers in the pathogenesis of asthma, and this year Yu and his colleagues found that the expression of ORMDL3 was significantly positively correlated with those of p‐ERK and MMP‐9 in an asthma mouse model, suggesting ORMDL3 is associated with airway remodeling in asthma via the ERK/MMP‐9 pathway . Given the involvement of ORMDL3 in regulating airway remodeling in asthma, the possible mechanisms have to be clarified subsequently in not only airway remodeling but also vascular remodeling in atherosclerosis.…”