The Involvement Of HB-EGF In Airway Smooth Muscle Remodeling Of Asthma

Airway smooth muscle(ASM) remodeling is the most important feature of airway remodeling in asthma, which is described as an increased ASM mass due to various structural and functional alterations including: proliferation/hyperplasia, migration and immunomodulatory capability of ASM cells. Increased cell number in muscle bundles may be due to immigration of circulating CD34+smooth muscle precursor cells or migration of proliferating cells within the muscle bundles. However, little information is available regarding the cellular mechanism. Heparin-binding epidermal growth factor (HB-EGF), a potent mitogen and chemotactic factor for smooth muscle cells in the EGF family, is significantly up-regulated in asthmatic airways and supposed to be a good biomarker of increased ASM mass. Our previous study also demonstrated that HB-EGF could induce the proliferation of ASM cells to aggravate the airway remodeling. Thus, wemove on to investigate its role in the migration of ASM cells and smooth muscle progenitor cells.We established mouse models of prolonged allergen challenge following airway instillation of mouse HB-EGF protein, adoptive transfer of smooth muscle progenitor cells and migration assay in vitro to explore the effect of HB-EGF in ASM migration. We found that:1) Boyden Chamber assay showed that HB-EGF can induce the migration of ASM cells in vitro in a dosage-dependent manner. EGFR inhibitor and p38inhibitor can blockage the migration butnot ERK1/2inhibitor, which indicated that HB-EGF can activate EGFR/p38pathway to induce the migration of ASM cells.2) We cultured the smooth muscle progenitor cells in vitro, and after fluorescence labeling, weinjected them into caudal vein. Simultaneously, we instilled HB-EGF protein into the airways and challenged these mice with OVA. The result showed that smooth muscle progenitor cells were obviously assembled in the injured airway of the asthmatic mice, suggesting that HB-EGF can induce the migration of smooth muscle progenitor cells in vivo. In conclusion, HB-EGF can induce the migration of circulating smooth muscle progenitor cells into asthmatic airways and the local ASM cells, which contribute to the thickening of ASM mass.