Overexpression of Neutrophil MMP-9 and HIF-1α May Contribute to the Finger-Like Projections Formation and Histo-Pathogenesis in Nasal Inverted Papilloma

Abstract

Tao Li,1,2 Kai Sen Tan,2– 5 Yan Yi Tu,1,2 Li Zhao,6 Jing Liu,2,3 Hsiao Hui Ong,2,3 De Yun Wang,2,3 Li Shi1 1Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 2Department of Otolaryngology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; 3National University Health System Infectious Diseases Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; 4Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; 5Biosafety level 3 Core Facility, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore, Singapore; 6Department of Otolaryngology, The Second Hospital of Shandong University, Shandong University, Jinan, People’s Republic of ChinaCorrespondence: Li ShiDepartment of Otolaryngology, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, Duanxing West Road, Jinan, Shandong, 250033, People’s Republic of ChinaTel [phone]Fax [phone]Email [email protected] Yun WangDepartment of Otolaryngology, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, Singapore, 119228 Tel [phone]Fax [phone]Email [email protected]: Nasal inverted papilloma (NIP) is defined based on its histological characteristic of inverted epithelium growth into the stroma. The inversion can result in epithelial growth in the underlying connective tissue stroma when the basement membrane completely separates from the epithelial layer. To date, such inversion mechanism underlying NIP’s pathological phenomenon is unknown. Therefore, we hypothesized that mediators and soluble proteins released by neutrophils, the most predominant infiltrating cells in NIP, is vital in causing the epithelial changes and pathogenesis of NIP.Methods: We collected 37 NIP tissues from patients who underwent surgical removal of NIP and performed hematoxylin–eosin (HE), immunohistochemical, and immunofluorescence staining to analyze in-depth the basic characteristics of NIP, including detecting the expression and distribution of MMPs and associated factors in NIP. Western blotting and quantitative real-time PCR were further performed to analyze the protein and mRNA expression levels of specific factors including MMPs, HIF-1α, and tissue inhibitors of metalloproteinases (TIMPs).Results: We observed finger-like projections that insert into the epithelium in NIP tissue as its main characteristics. The projections contain fibroblasts, extracellular matrix, capillaries, and infiltrating inflammatory cells. We found abundant neutrophils clustered at the finger-like projection of NIP, and also noted MMP-1 and MMP-9 were up-regulated in NIP (p< 0.05), whereas TIMP-1/3 was decreased. The expression level of HIF-1α was also found to be increased in NIP tissue. We further showed that MMP-9 and HIF-1α were mainly expressed by neutrophils and were predominantly observed in the finger-like projections that contribute to the NIP pathology.Conclusion: Upregulation and release of MMP-9 and HIF-1α from infiltrating neutrophils may cause damage to the epithelial basement membrane and epithelial clefts, forming finger-like projections with angiogenesis and fibroblasts insertion, resulting in epithelial growth in the tissue stroma, a typical histo-pathological characteristic in NIP.Keywords: nasal inverted papilloma, finger-like projection, MMP-9, HIF-1α, pathogenesis, neutrophils

Keywords

• nasal inverted papilloma
• finger-like projection
• mmp-9
• hif-1α
• pathogenesis
• neutrophils