Lipoxin A4 regulates epithelial-mesenchymal transition in epithelial cell through inhibiting activation of ERK1/2 pathway
LUO Yacan1, WU Zhenjie2, JIN Minli1, LOU Lejing1, YANG Song1, CAI Jihao1, CAIChang1.
1.Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, China; 2.Department of Pulmonary, Taizhou Hospital, Taizhou 317000,China
LUO Yacan,WU Zhenjie,JIN Minli, et al. Lipoxin A4 regulates epithelial-mesenchymal transition in epithelial cell through inhibiting activation of ERK1/2 pathway[J]. JOURNAL OF WEZHOU MEDICAL UNIVERSITY, 2022, 52(6): 446-452.
Abstract：Objective: To investigate the effects of lipoxin A4 (LXA4) on transforming growth factor β1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) in BEAS-2B (human normal bronchial epithelial cell) and ovalbumin (OVA)-induced airway remodeling in asthmatic mice and its possible mechanism. Methods: The BALB/c mice were randomly divided into 4 groups: control group, OVA group, LXA4 group and OVA+ LXA4 group. The pathological changes of lung tissues were observed by HE and PAS staining. BEAS-2B cells were divided into 6 groups: control group, interleukin (IL)-4 group, IL-13 group, TGF-β1 group, IL-4/IL-13/TGF-β1 co-stimulation group and LXA4 pretreatment group. The mRNA expression of α-smooth muscle actin (α-SMA), E-cadherin were detected by quantitative real time PCR. α-SMA, E-cadherin, ERK1/2 and pERK1/2 protein expressions were measured by Western blot. Results: Compared with the control group, the lungs in the model group exhibited observable lung histopathologic changes, including alveolar wall thickening, interstitial edema, inflammatory infiltration, hemorrhage, and lung tissue destruction. In addition, mice in the OVA group showed strong AB/PAS-positive staining in their bronchial epithelial tissues, which indicated goblet cell hyperplasia and mucus production, but LXA4 significantly improved the above-mentioned pathological changes.In BEAS-2B, compared with control group, cells treated with TGF-β1 for 72 hours became spindle-shaped, loosely attached, and cell intercellular spaces-enlarged. Cells stimulated by a combination of TGF-β1, IL-4 and IL-13 exhibited increased morphological alterations, compared with the TGF-β1 group. Compared with controlgroup, the expression of α-SMA mRNA and protein and pERK protein increased, while expression of E-cadherinmRNA and protein decreased in TGF-β1 group. α-SMA and pERK increased while E-cadherin decreased in theTGF-β1/IL-4/IL-13 co-stimulation group more significantly than the TGF-β1 group. Meanwhile, LXA4 inhibitedthe increase of TGF-β1, IL-4, IL-13 co-stimulation-induced α-SMA and the decrease of E-cadherin, and reducedERK phosphorylation in BEAS 2B cells. Conclusion: LXA4 could inhibit OVA-induced airway remodeling inasthma mouse models. Th2 cytokines IL-4 and IL-13 are condusive to EMT in BEAS-2B cells. LXA4 inhibitsEMT in airway epithelial cells, which may depend on the blocking of ERK1/2 pathway phosphorylation.
