epidermal-growth-factor and Sinusitis

The pathogenesis of chronic rhinosinusitis (CRS) is largely unknown, but accumulating evidence supports the role of the airway epithelium in its pathophysiology. In our study here, we evaluated whether epidermal growth factor (EGF) regulates a hypoxia-inducible factor 1α (HIF-1α)-microRNA-21 (miR-21)-aquaporin 4 (AQP4) axis in nasal epithelial cells from CRS patients. We found that, compared with normal sinus mucosa, EGF, HIF-1α, and miR-21 were upregulated and AQP4 was downregulated in sinus mucosa from patients with CRS and in a CRS mouse model. It was established that EGF upregulated HIF-1α and miR-21 expression, that HIF-1α regulated miR-21 transcription, and that the AQP4 gene was a target of miR-21. Knockdown of EGF and HIF-1α mRNAs and of miR-21, or overexpression of AQP4 mRNA, inhibited proliferation and promoted apoptosis of hypoxia-exposed human nasal epithelial cells, effects that were associated with reduced levels of α-SMA, fibronectin, and vimentin, as well as promoted caspase-3 activity and E-cadherin levels. In the mouse CRS model, EGF elevation increased in vivo production of inflammatory IL-4 and IFN-γ to promote CRS, which was reversed by AQP4 elevation. Collectively, EGF upregulates HIF-1α and miR-21 expression to inhibit AQP4 expression, thereby promoting the proliferation of nasal epithelial cells and the development of CRS.

Topics: Animals; Aquaporin 4; Epidermal Growth Factor; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; MicroRNAs; RNA, Messenger; Sinusitis

The pathogenesis of chronic rhinosinusitis (CRS) remains unclear to date. The tissue remodeling in nasal polyps may be the result of inflammatory mediators and may involve epithelial-mesenchymal transition (EMT) and EMT-associated features such as cell motility in nasal epithelial cells (NECs). We determined whether NEC in nasal polyps of CRS already display features of EMT in vivo or respond with EMT to growth factor stimulation in vitro. Nasal polyp tissues expressed both epithelial and mesenchymal markers. Primary NEC from inferior turbinates and nasal polyps responded to the EMT-inducing agents transforming growth factor (TGF)-β1 and epidermal growth factor (EGF) with different expression patterns of EMT markers (E-cadherin, N-cadherin, Snail, Slug, Twist), however, only NEC from nasal polyps were susceptible to TGF-β1 and EGF-dependent cell migration. Our data suggest that a partial EMT is associated with the pathogenesis of nasal polyps in CRS patients. Furthermore, we show for the first time that epithelial cells from both nasal polyps and inferior turbinates were able to undergo an EMT-like process following exposure to TGF-β1 or EGF in vitro but that only NEC from nasal polyps responded with enhanced cell motility. Our data suggest that NEC from CRS patients have undergo partial EMT and that this process may be involved in the pathogenesis of CRS.

Topics: Adult; Aged; Aged, 80 and over; Cell Movement; Epidermal Growth Factor; Epithelial Cells; Epithelial-Mesenchymal Transition; Female; Gene Expression Profiling; Humans; Inflammation; Male; Middle Aged; Nasal Polyps; Oligonucleotide Array Sequence Analysis; Sinusitis; Transforming Growth Factor beta1; Turbinates; Young Adult

Aberrant epithelial repair has been observed in chronic rhinosinusitis (CRS) patients; however, the mechanism of epithelial cell repair regulation is unclear. Epidermal growth factor (EGF) plays an important role in regulating epithelial cell repair in lower airway and may be a critical factor in the remodeling processes of CRS. The objective of our research is to evaluate the differences between CRS and normal subjects and between chronic rhinosinusitis without nasal polys (CRSsNP) and chronic rhinosinusitis with nasal polys (CRSwNP) in the regulation of EGF pathways and the regulating proliferative position of classic Ras/Raf/MEK/ERK pathways.. We evaluated the proliferation rates of ethmoidal mucosal cells before and after stimulation with EGF, epidermal growth factor receptor (EGFR) kinase inhibitor AG1478, and extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor PD98059 using MTT assays. We also analyzed the sinonasal epithelial cells collected from control subjects and patients with CRS subtypes CRSsNP and CRSwNP for the expression of ERK1/2, phosphorylated ERK1/2, P21, P15, and P27 using western blotting analyses.. The proliferation rates of sinonasal epithelial cells before and after EGF stimulation were lower in CRS patients than in the controls. AG1478 or PD98059 inhibitor treatment of control epithelial cells did not result in a significant difference in proliferation. Although, AG1478 and PD98059 inhibited the proliferation of CRS cells, the degree of proliferation inhibition was markedly different in CRSsNP. AG1478 suppressed the proliferation of CRSwNP epithelial cells, whereas PD98059 had no effect. The ratio of ERK1/2 phosphorylation in CRS cells was lower than that of the control cells. Cyclin-dependent kinase inhibitors were highly expressed in CRS cells compared with that of control cells. ERK1/2 and P27 showed differential expression in CRSsNP and CRSwNP.. Differences existed in EGF pathways in CRS patients and normal subjects as well as in CRSsNP and CRSwNP. Classical Ras/Raf/MEK/ERK pathway may assume absolute superiority in control cells. Ras/Raf/MEK/ERK classical pathway and other pathways might be active at the same time to stimulate epithelial cell proliferation in CRSsNP. The function of Ras/Raf/MEK/ERK classical pathway was weaker in CRSwNP than in CRSsNP and when the classical pathway was blocked in CRSwNP, some other pathway could have completely compensated the proliferation induced by the Ras/Raf/MEK/ERK pathway.

Topics: Adult; Aged; Cell Proliferation; Cells, Cultured; Epidermal Growth Factor; Epithelial Cells; Female; Humans; Male; Middle Aged; Nasal Mucosa; Sinusitis

To evaluate the changes of epidermal growth factor (EGF) in serum before and after endoscopic surgery in patients with chronic sinusitis, and then to explore its clinical significance.. Serum was collected before and after operation and EGF concentrations were measured by the radioimmunoassay at different times.. EGF levels in patients with chronic sinusitis (1.24 +/- 0.41) microg/L were higher than that in control group (0.92 +/- 0.23) microg/L, but there were no significantly difference between them (P > 0.05). The concentrations of EGF were reduced after surgery, and the lowest were evaluated after 4 weeks. Significant difference of EGF concentrations were found between before and 4 weeks after operation (P < 0.01). The concentration of EGF were raised 6 weeks after surgery, and returned to normal after 8 weeks.. The changes of EGF in serum before and after endoscopic surgery may relate with the epithelization process of sinus mucosa after endoscopic surgery.

Topics: Adult; Case-Control Studies; Chronic Disease; Endoscopy; Epidermal Growth Factor; Female; Humans; Male; Middle Aged; Sinusitis; Treatment Outcome; Young Adult

To investigate the expression of epidermal growth factor receptor (EGFR) messenger RNA (mRNA) in human sinus mucosa and to compare the expression of EGFR and EGF among patients with chronic rhinosinusitis (CRS), patients with CRS and nasal polyposis (CRS/NP), and a healthy control group.. Maxillary sinus ostia mucosa was harvested from patients undergoing endoscopic sinus surgery for CRS or CRS/NP and from patients undergoing surgery for non-CRS pathologic conditions (control group). The samples were analyzed using semiquantitative reverse transcription-polymerase chain reaction to detect mRNA of EGFR. Hematoxylin-eosin staining and immunofluorescent staining were used to localize EGFR and EGF in the sinus mucosa.. Academic research.. Three groups (CRS, CRS/NP, and control), each with 10 subjects, were enrolled in the present study.. Area ratios of positive cells in the epithelia were compared among the CRS, CRS/NP, and control groups. In addition, eosinophils were counted in the subepithelial connective tissue in the 3 groups.. The level of EGFR mRNAs in the sinus mucosa of the CRS and CRS/NP groups was statistically significantly increased compared with that in the control group (P < .01), and no statistically significant difference was found between the sinus mucosa of the CRS group and that of the CRS/NP group (P < .01). On hematoxylin-eosin staining, hyperplasia and metaplasia of epithelial goblet cells were present in the sinus mucosa of the CRS and CRS/NP groups. Epidermal growth factor receptor was mainly expressed in goblet cells and basal cells and was weakly expressed in ciliated cells, while EGF expression was located in epithelial cells and in some inflammatory cells but not in goblet cells. In the control group, expression of EGFR and EGF was lower compared with that in the CRS and CRS/NP groups. No statistically significant area ratios of positive cells differences in staining of EGFR and EGF were found between the CRS group and the CRS/NP group (P > .05), whereas statistically significant differences were found between the control group and the 2 CRS groups (P < .01). The number of eosinophils was statistically significantly increased in the CRS/NP group compared with that in the CRS group (P < .01).. Up-regulation of the EGFR cascade may have an important role regarding mucus production in the sinus mucosa of patients with CRS and CRS/NP associated with hyperplasia and metaplasia of epithelial goblet cells.

Topics: Case-Control Studies; Chronic Disease; Eosinophils; Epidermal Growth Factor; ErbB Receptors; Humans; Leukocyte Count; Nasal Mucosa; Nasal Polyps; Rhinitis; RNA, Messenger; Sinusitis