国際シンポジウム５（鼻科２）

Chronic rhinosinusitis(CRS)is one of the most common chronic diseases and represents a major public health problem all over the world.CRS is typically divided into two subtypes based on the absence or presence of nasal polyps, which are described as CRS without nasal polyps(CRSsNP)and CRS with nasal polyps(CRSwNP)respectively.In Western countries, nasal mucosa in CRSsNP shows predominant infiltration of neutrophils, while nasal polyps in CRSwNP is characterized by eosinophilc infiltration.Recently, the number of cases of intractable CRSwNP that have immediately recurred after ESS has increased in Japan.The pathology of nasal polyps in these refractory CRSwNP patients shows strong eosinophilic infiltration.Thus, our study defined intractable CRSwNP as eosinophilic chronic rhinosinusitis(ECRS) .Our laboratory reported the precise definition of ECRS as being of a refractory and recurrence nature in CRSwNP, consistent with the approach taken by a large-scale epidemiological survey called the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis(JESREC) .In this study, cases with more than 70/HPF of eosinophils in the nasal polyps were significantly correlated with the recurrence of nasal polyps after ESS, and were classified as having ECRS.We also defined ECRS as CRSwNP with bilateral disease, the presence of nasal polyps, blood eosinophilia, and dominant shadow of ethmoid sinuses in CT scans, as an algorithm to classify CRS prognosis before ESS.This classification has been widely used in Japan.Patients with non-ECRS show good response to ESS, despite ECRS being intractable.It is very hard to treat ECRS, and little is known about its pathogenesis.We compared the gene expression levels in nasal polyps with those in inferior turbinates of patients with CRSwNP using RNA-seq.We found an increase of Cystatin SN(CST1)expression in the nasal polyps from patients with CRSwNP.CST1 is known to be part of the type 2 cystatin subfamily and is expressed in the normal salivary glands, gall bladder, and ureter, and so on.CST1 has a role as a protease inhibitor and inhibits cysteine protease activity by binding tightly with cysteine protease.On the other hand, some studies have shown that CST1 plays an important role in the processes of inflammation and tumorigenesis.In fact, CST1 is highly expressed in various cancer cells, and is elevated in the serum and urine of patients with colorectal cancer.In this study, we investigated the expression of CST1 in nasal polyps from patients with ECRS and analyzed the expression of CST1 according to disease severity classification in patients with ECRS.In addition, we examined the function of CST1 in epithelial cells and fibroblasts of nasal polyps in association with factors induced Th2 inflammation.CST1 was significantly expressed in the epithelial cells of the nasal polyps from patients with ECRS, compared with patients with non-ECRS.Particularly, CST1 showed very strong expression in patients with severe ECRS.The expression of CST1 may be correlated with the recurring and refractory nature of ECRS.We examined the function of CST1 using nasal epithelial cells and nasal fibroblasts.Stimulation by a combination of IL-4 plus dsRNA plus CST1 significantly elevated mRNA expression levels and protein levels of TSLP in nasal epithelial cells.Stimulation by TSLP or IL-33 significantly elevated mRNA expression levels of CST1 in nasal epithelial cells.Stimulation of CST1 significantly elevated mRNA expression levels of CCL11 and POSTN in nasal fibroblasts.CST1 could amplify eosinophilic infiltration and Th2 inflammation by interacting with epithelial-derived cytokines and fibroblasts on nasal polyps.CST1 may be involved in the pathogenesis of ECRS, and may contribute to the severity and recurrence of CRSwNP after ESS.