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Involvement of B2 receptor in bradykinin-induced proliferation and proinflammatory effects in human nasal mucosa-derived fibroblasts isolated from chronic rhinosinusitis patients.

Tsai YJ, Hao SP, Chen CL, Lin BJ, Wu WB - PLoS ONE (2015)

Bottom Line: Accordingly, the B2R was preferentially expressed in the NMDFs than B1R.Collectively, we report here for the first time that fibroblasts, KNG/BK, and BKRs are overexpressed in CRSsNP mucosa and BK upregulates chemokine expression, proliferation, and proinflammatory molecule expression in NMDFs via B2R activation, which lead to a functional increase in monocyte-fibroblast interaction.Our findings reveal a critical role of fibroblast, KNG/BK, and BKRs in the development of CRSsNP.

View Article: PubMed Central - PubMed

Affiliation: Department of Otolaryngology Head and Neck Surgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan; Department of Chemistry, Graduate Institute of Applied Science and Engineering, College of Science and Engineering, Fu-Jen Catholic University, New Taipei City, Taiwan; Graduate Institute of Basic Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan; School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan.

ABSTRACT
Chronic rhinosinusitis (CRS) is a chronic inflammatory disease of the sinonasal mucosa either accompanied by polyp formation (CRSwNP) or without polyps (CRSsNP). CRSsNP accounts for the majority of CRS cases and is characterized by fibrosis and neutrophilic inflammation. However, the pathogenesis of CRS, especially CRSsNP, remains unclear. Immunohistochemistry of CRSsNP specimens in the present study showed that the submucosa, perivascular areas, and the mucous glands were abundant in fibroblasts. Therefore, we investigated the effects bradykinin (BK), an autacoid known to participate in inflammation, on human CRSsNP nasal mucosa-derived fibroblasts (NMDFs). BK increased CXCL1 and -8 secretion and mRNA expression with EC50 ranging from 0.15~0.35 μM. Moreover, BK enhanced cell proliferation and upregulated the expressions of proinflammatory molecules, including cell adhesion molecules (CAMs) and cyclooxygenase (COX)-1 and -2. These functionally caused an increase in monocyte adhesion to fibroblast monolayer. Using pharmacological intervention and BKR siRNA knockdown, we demonstrated that the BK-induced CXCL chemokine release, cell proliferation and COX and CAM expressions were mainly through the B2 receptor (B2R). Accordingly, the B2R was preferentially expressed in the NMDFs than B1R. The B2R was highly expressed in the CRSsNP than the control specimens, while the B1R and kininogen (KNG)/BK expression slightly increased in the CRSsNP mucosa. Collectively, we report here for the first time that fibroblasts, KNG/BK, and BKRs are overexpressed in CRSsNP mucosa and BK upregulates chemokine expression, proliferation, and proinflammatory molecule expression in NMDFs via B2R activation, which lead to a functional increase in monocyte-fibroblast interaction. Our findings reveal a critical role of fibroblast, KNG/BK, and BKRs in the development of CRSsNP.

No MeSH data available.


Related in: MedlinePlus

Effects of BKR antagonism on CXCL1 and -8 secretion and cell proliferation.(A) NMDFs were treated with BK in the presence of vehicle or the indicated concentrations of HOE140 or R715 for 16 h, (A) the medium was collected and CXCL1 and -8 secretion was determined by ELISA (n = 3–4) and (B) the remaining adherent cells were determined by the MTT assay to measure cell proliferation (n = 4). *P<0.05 versus BK control.
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pone.0126853.g005: Effects of BKR antagonism on CXCL1 and -8 secretion and cell proliferation.(A) NMDFs were treated with BK in the presence of vehicle or the indicated concentrations of HOE140 or R715 for 16 h, (A) the medium was collected and CXCL1 and -8 secretion was determined by ELISA (n = 3–4) and (B) the remaining adherent cells were determined by the MTT assay to measure cell proliferation (n = 4). *P<0.05 versus BK control.

Mentions: Next, we examined which receptor is responsible for CXC chemokine release and cell proliferation by BK in NMDFs. As shown in Fig 5A, NMDFs were treated with the indicated concentrations of HOE140 or R715, two selective antagonists for B2R and B1R respectively. After which, the cells were treated with BK and the secretion of CXCL1 and -8 was measured. HOE140 inhibited the secretion of CXCL1 and -8 in a concentration-dependent manner. The inhibition was achieved at 100 nM and almost reached a maximum at 500 nM. However, R715, did not inhibit BK-induced CXCL1 and -8 secretion. Similarly, HOE140 (0.01 μM) was sufficient to inhibit BK-induced cell proliferation, while R715 at a higher concentration (4 μM) did not exhibit any inhibitory effect on BK-induced cell proliferation.


Involvement of B2 receptor in bradykinin-induced proliferation and proinflammatory effects in human nasal mucosa-derived fibroblasts isolated from chronic rhinosinusitis patients.

Tsai YJ, Hao SP, Chen CL, Lin BJ, Wu WB - PLoS ONE (2015)

Effects of BKR antagonism on CXCL1 and -8 secretion and cell proliferation.(A) NMDFs were treated with BK in the presence of vehicle or the indicated concentrations of HOE140 or R715 for 16 h, (A) the medium was collected and CXCL1 and -8 secretion was determined by ELISA (n = 3–4) and (B) the remaining adherent cells were determined by the MTT assay to measure cell proliferation (n = 4). *P<0.05 versus BK control.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4430235&req=5

pone.0126853.g005: Effects of BKR antagonism on CXCL1 and -8 secretion and cell proliferation.(A) NMDFs were treated with BK in the presence of vehicle or the indicated concentrations of HOE140 or R715 for 16 h, (A) the medium was collected and CXCL1 and -8 secretion was determined by ELISA (n = 3–4) and (B) the remaining adherent cells were determined by the MTT assay to measure cell proliferation (n = 4). *P<0.05 versus BK control.
Mentions: Next, we examined which receptor is responsible for CXC chemokine release and cell proliferation by BK in NMDFs. As shown in Fig 5A, NMDFs were treated with the indicated concentrations of HOE140 or R715, two selective antagonists for B2R and B1R respectively. After which, the cells were treated with BK and the secretion of CXCL1 and -8 was measured. HOE140 inhibited the secretion of CXCL1 and -8 in a concentration-dependent manner. The inhibition was achieved at 100 nM and almost reached a maximum at 500 nM. However, R715, did not inhibit BK-induced CXCL1 and -8 secretion. Similarly, HOE140 (0.01 μM) was sufficient to inhibit BK-induced cell proliferation, while R715 at a higher concentration (4 μM) did not exhibit any inhibitory effect on BK-induced cell proliferation.

Bottom Line: Accordingly, the B2R was preferentially expressed in the NMDFs than B1R.Collectively, we report here for the first time that fibroblasts, KNG/BK, and BKRs are overexpressed in CRSsNP mucosa and BK upregulates chemokine expression, proliferation, and proinflammatory molecule expression in NMDFs via B2R activation, which lead to a functional increase in monocyte-fibroblast interaction.Our findings reveal a critical role of fibroblast, KNG/BK, and BKRs in the development of CRSsNP.

View Article: PubMed Central - PubMed

Affiliation: Department of Otolaryngology Head and Neck Surgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan; Department of Chemistry, Graduate Institute of Applied Science and Engineering, College of Science and Engineering, Fu-Jen Catholic University, New Taipei City, Taiwan; Graduate Institute of Basic Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan; School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan.

ABSTRACT
Chronic rhinosinusitis (CRS) is a chronic inflammatory disease of the sinonasal mucosa either accompanied by polyp formation (CRSwNP) or without polyps (CRSsNP). CRSsNP accounts for the majority of CRS cases and is characterized by fibrosis and neutrophilic inflammation. However, the pathogenesis of CRS, especially CRSsNP, remains unclear. Immunohistochemistry of CRSsNP specimens in the present study showed that the submucosa, perivascular areas, and the mucous glands were abundant in fibroblasts. Therefore, we investigated the effects bradykinin (BK), an autacoid known to participate in inflammation, on human CRSsNP nasal mucosa-derived fibroblasts (NMDFs). BK increased CXCL1 and -8 secretion and mRNA expression with EC50 ranging from 0.15~0.35 μM. Moreover, BK enhanced cell proliferation and upregulated the expressions of proinflammatory molecules, including cell adhesion molecules (CAMs) and cyclooxygenase (COX)-1 and -2. These functionally caused an increase in monocyte adhesion to fibroblast monolayer. Using pharmacological intervention and BKR siRNA knockdown, we demonstrated that the BK-induced CXCL chemokine release, cell proliferation and COX and CAM expressions were mainly through the B2 receptor (B2R). Accordingly, the B2R was preferentially expressed in the NMDFs than B1R. The B2R was highly expressed in the CRSsNP than the control specimens, while the B1R and kininogen (KNG)/BK expression slightly increased in the CRSsNP mucosa. Collectively, we report here for the first time that fibroblasts, KNG/BK, and BKRs are overexpressed in CRSsNP mucosa and BK upregulates chemokine expression, proliferation, and proinflammatory molecule expression in NMDFs via B2R activation, which lead to a functional increase in monocyte-fibroblast interaction. Our findings reveal a critical role of fibroblast, KNG/BK, and BKRs in the development of CRSsNP.

No MeSH data available.


Related in: MedlinePlus