Potential Involvement of the Epidermal Growth Factor Receptor Ligand Epiregulin and Matrix Metalloproteinase-1 in Pathogenesis of Chronic Rhinosinusitis

Abstract

Chronic rhinosinusitis (CRS) is a heterogeneous chronic inflammatory disease of the nose and paranasal sinuses that presents without or with nasal polyps (CRSwNP). Notable features of CRSwNP are the frequent presence of type 2 allergic inflammation and high prevalence of Staphylococcus aureus (SA) colonization. As inflammation persists, sinus tissue undergoes epithelial damage and repair along with polyp growth, despite active medical management. Because one feature of damaged tissue is enhancement of growth factor signaling, we evaluated the presence of epidermal growth factor receptor (EGFR) ligands and matrix metalloproteinases (MMPs) in CRS. The objectives of this study were to analyze the expression of EGFR ligands and MMPs in patients with CRS and to investigate the possible role of SA on epithelial activation. Sinonasal tissues were collected during surgery from control subjects and patients with CRS. Tissues were processed as described previously for analysis of mRNA (RT-PCR) and proteins (ELISA) for the majority of EGFR ligands within the tissue extracts. CRS tissue was used for evaluation of the distribution of epiregulin (EREG), an EGFR ligand, and MMP-1 by immunohistochemistry. In parallel studies, expression of these genes and proteins was analyzed in cultured primary airway epithelial cells. Elevated expression of EREG and MMP-1 mRNA and protein was observed in uncinate and polyp tissue from patients with CRSwNP. Immunohistochemistry study of clinical samples revealed that airway epithelial cells expressed both of these proteins. Cultured primary human airway epithelial cells expressed MMP-1, and MMP-1 was further induced by stimulation with EREG or heat-killed SA (HKSA). The induction of MMP-1 by HKSA was blocked by an antibody against EREG, suggesting that endogenous EREG induces MMP-1 after stimulation with HKSA. EREG and MMP-1 were found to be elevated in nasal polyp and uncinate tissues in patients with CRSwNP. Elevated expression of EREG and MMP-1 may be related to polyp formation in CRS, and colonization of SA might further enhance this process.

Beneficial Effect of Early Intervention with Garenoxacin for Bacterial Infection-Induced Acute Exacerbation of Bronchial Asthma and Chronic Obstructive Pulmonary Disease

“…This suppression mechanism of GRNX, shown in the inhibition of phospho-ERK1/2, again suggests that GRNX affects not only infected bacterium, but airway and local inflammatory cells. We have recently shown, together with previous findings, that GRNX may inhibit S. aureus -related inflammation as well [32]. Further study is warranted to elucidate the anti-inflammatory effect of GRNX on bacterial- and respiratory disease-related responses.…”

The Development of Dry Eye Disease after Surgery-Indicated Chronic Rhinosinusitis: A Population-Based Cohort Study

“…On the other hand, the vicious cycle in developing DED includes components such as meibomian gland dysfunction (MGD), aqueous deficiency, exposure-related damage and goblet cell deficiency [12]. Among them, both the MGD and goblet cell deficiency are related to the increment inflammatory reaction [12,19], in which MGD will lead to the evaporative excess subtype of DED and affects about 50 percent of patients with DED [20]. Besides, several inflammatory mediators-like interleukin and matrix metalloproteinases-are elevated in those individuals with DED [12,21].…”

Airway Epithelial Dynamics in Allergy and Related Chronic Inflammatory Airway Diseases

“…The EMT process is driven by an array of factors such as WNT, reactive oxygen species, proteases, HIF1, IL-13 Epiregulin, Oncostatin M, and IL-1 (Oyer et al, 2013;Batzakakis et al, 2014;Schleimer, 2017;Aazami et al, 2018;Yang et al, 2018;Tomaszewska et al, 2019). CRSwNP patients have altered expression levels of EMT related factors, such as MMP-1 (Malinsky et al, 2013;Homma et al, 2017), MMP-2 (Malinsky et al, 2013), TIMP-1 (Wang et al, 2012;Muluk et al, 2015), MMP-7 (Yang et al, 2017;Chen et al, 2018), MMP-9 (Wang et al, 2012;Malinsky et al, 2013;Yeo et al, 2013;Li et al, 2015;Muluk et al, 2015;Chen et al, 2018;Suzuki et al, 2018;Xiang et al, 2019), TIMP-2 (Li et al, 2015) E-cadherin (Hupin et al, 2014;Kim et al, 2018;Deng et al, 2019). BMT is associated with duration of inflammation independent of tissue eosinophilia (Kountakis et al, 2004;Kuhar et al, 2017).…”