title: LL-37 secreted by epithelium promotes fibroblast collagen production: a potential mechanism of small airway remodeling in chronic obstructive pulmonary disease.
abstract: Emerging evidence suggests that the process of small airway remodeling is mediated by profibrotic growth factors produced by epithelium, which are capable of activating the underlying mesenchymal cells with excessive collagen production. It has been demonstrated that human cathelicidin antimicrobial protein LL-37 is highly expressed in small airway epithelium from COPD patients. However, it is unknown whether the increased levels of LL-37 in epithelium are involved in the pathogenesis of small airway remodeling in COPD. In this study, we examined the expression of LL-37 in small airways from smokers with COPD and controls (non-smokers and smokers without COPD) by immunohistochemistry, and then the association between LL-37 expression in epithelium and the structural changes of small airway remodeling was analyzed. In vitro, the effect of CSE-induced epithelial secretion of LL-37 on collagen production in human lung fibroblasts (HFL-1 cell line) was studied in a co-culture system. Finally, the signaling pathways involved in the effect of LL-37 on fibroblast collagen production were evaluated. The results showed that LL-37 immunoreactivity in airway epithelium was significantly elevated in smokers with COPD compared with controls. In addition, the magnitude of LL-37 expression in epithelium was positively correlated with airway wall thickness and collagen deposition. In vitro, CSE-induced epithelial secretion of LL-37 promoted fibroblast collagen production. Finally, we showed that formyl peptide receptor-like 1 (FPRL1)-dependent extracellular signal-regulated kinase (ERK) signaling pathway was essential for LL-37-induced collagen production in HFL-1 cells. These results suggest that after cigarette smoke exposure, the increased levels of LL-37 in airway epithelium could stimulate collagen production in the underlying lung fibroblasts and may contribute to small airway remodeling in COPD.
authors: Department of Respiratory Medicine, Qilu Hospital, Shandong University, Jinan, China.
authors: Congcong
authors: C
authors: Sun
authors: Department of Radiation Toxicology and Oncology, Beijing Institute of Radiation Medicine, Beijing, China.
authors: Maoxiang
authors: M
authors: Zhu
authors: Department of Radiation Toxicology and Oncology, Beijing Institute of Radiation Medicine, Beijing, China.
authors: Zhihua
authors: Z
authors: Yang
authors: Department of Radiation Toxicology and Oncology, Beijing Institute of Radiation Medicine, Beijing, China.
authors: Xiujie
authors: X
authors: Pan
authors: Department of Respiratory Medicine, Qilu Hospital, Shandong University, Jinan, China.
authors: Yuke
authors: Y
authors: Zhang
authors: Department of Respiratory Medicine, Qilu Hospital, Shandong University, Jinan, China.
authors: Qin
authors: Q
authors: Wang
authors: Department of Respiratory Medicine, Qilu Hospital, Shandong University, Jinan, China.
authors: Wei
authors: W
authors: Xiao
mesh_terms: D000328:Adult; D056151:Airway Remodeling; D000595:Amino Acid Sequence; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D001483:Base Sequence; D016022:Case-Control Studies; D002460:Cell Line; D003094:Collagen / Q000096:biosynthesis*; D017931:DNA Primers; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D029424:Pulmonary Disease, Chronic Obstructive / Q000503:physiopathology*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012907:Smoking; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D017931:DNA Primers; D003094:Collagen; D054804:Cathelicidins