tretinoin and Nasal-Polyps

Chronic rhinosinusitis with nasal polyps (CRSwNP) is usually treated with corticosteroids, given their anti-inflammatory effects. Unlike the nasal administration, the oral and ocular use of tretinoin, an immunoregulatory drug, is well established. Therefore, tretinoin was thought to act on nasal polyps, and possible adverse and/or therapeutic effects were investigated.. A first-in-human open-label trial was conducted enrolling patients with CRSwNP randomized into: a control group (CTR, n = 15), treated with budesonide for 24 weeks; and an intervention group (TRT, n = 15), who received budesonide and 0.1% tretinoin in the last 12 weeks. Primary endpoint included histopathological analysis and tissue immunoassay (Multiplex) for tumor necrosis factor α (TNF-α), interleukin (IL)-1β, IL-4, IL-5, IL-13, and matrix metalloproteinase 9 (MMP-9) at 12 and 24 weeks. Secondary endpoints were: adverse events report, endoscopy (modified Lund-Kennedy scoring system [LKS]), quality of life (22-item Sino-Nasal Outcome Test [SNOT-22]), and olfactory test (Connecticut Chemosensory Clinical Research Center) at baseline, at 12 weeks, and at 24 weeks, in addition to serum biochemistry and tomographic findings (Lund-Mackay computed tomography [CT] staging system [LMS]) at baseline and 24 weeks.. TRT showed less microscopic edema (2/13 [15.4%] vs 8/13 [61.5%]; p = 0.044) as well as no increase in cytokines levels. All adverse events were categorized as "grade 1" (asymptomatic; mild). The most interesting part of this study was the improvement in smell between baseline (T0) and week 24 (T2) in TRT only (p = 0.041).. Transnasal tretinoin associated with budesonide was safe and well tolerated, and it should be investigated as a treatment option for some CRSwNP endotypes. ©2021 ARSAAOA, LLC.

Topics: Chronic Disease; Humans; Nasal Polyps; Quality of Life; Rhinitis; Sinusitis; Tretinoin

Patients with aspirin-exacerbated respiratory disease (AERD) regularly exhibit severe nasal polyposis. Studies suggest that chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by excessive fibrin deposition associated with a profound decrease in epithelial tissue plasminogen activator (tPA). Retinoids, including vitamin A and its active metabolite retinoic acid (RA), are necessary for maintaining epithelial function and well-known inducers of tPA in endothelial cells.. This study sought to determine whether endogenous retinoids are involved in NP pathophysiology and disease severity in patients with CRSwNP and AERD.. NP tissue was collected from patients with AERD or CRSwNP, and concentrations of retinoids and fibrinolysis markers were measured using ELISA. Normal human bronchial epithelial cells were stimulated alone or in combination with RA and IL-13 for 24 hours.. This study observed lower retinoid levels in nasal polyps of patients with AERD than those with CRSwNP or healthy controls (P < .01). Levels of the fibrin-breakdown product d-dimer were the lowest in AERD polyps (P < .01), which is consistent with lower tPA expression (P < .01). In vitro, all-trans RA upregulated tPA levels in normal human bronchial epithelial cells by 15-fold and reversed the IL-13-induced attenuation of tPA expression in cultured cells (P < .01).. RA, a potent inducer of epithelial tPA in vitro, is reduced in tissue from patients with AERD, a finding that may potentially contribute to decreased levels of tPA and fibrinolysis in AERD. RA can induce tPA in epithelial cells and can reverse IL-13-induced tPA suppression in vitro, suggesting the potential utility of RA in treating patients with CRSwNP and/or AERD.

Topics: Asthma, Aspirin-Induced; Chronic Disease; Endothelial Cells; Fibrin; Fibrinolysis; Humans; Interleukin-13; Nasal Polyps; Rhinitis; Sinusitis; Tissue Plasminogen Activator; Tretinoin

All-trans retinoic acid (ATRA), a derivative of vitamin A, is known to have anti-fibrogenic effects and regulates cell proliferation and differentiation. Therefore, these abilities of ATRA may influence tissue remodeling in the upper airway. The aims of the present study were to investigate the effects of ATRA on the myofibroblast differentiation, extracellular matrix (ECM) production, cell migration, and collagen gel contraction and to determine the molecular mechanisms of ATRA in TGF-β1-induced nasal polyp-derived fibroblasts (NPDFs).. NPDFs were isolated from nasal polyp. Cytotoxicity was evaluated by 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide assay. TGF-β1-induced fibroblasts were pretreated with ATRA. The expression levels of alpha-smooth muscle actin (α-SMA), collagen type 1, fibronectin, phospho-mitogen-activated protein kinase, and p-p50 (nuclear factor-kappaB [NF-κB]) were measured by Western blot analysis, real-time polymerase chain reaction, and/or immunofluorescence staining. Cell migration was analyzed with cell migration scratch assay and Transwell migration assay. Collagen contractile activity was measured using a collagen gel contraction assay.. ATRA had no significant cytotoxic effect in NPDFs. Expression levels of α-SMA, collagen type 1, and fibronectin stimulated by TGF-β1 were significantly downregulated in the ATRA-pretreated fibroblasts. TGF-β1-induced cell migration and collagen gel contraction were significantly inhibited by ATRA pretreatment. ATRA also significantly inhibited phosphorylation of c-Jun N-terminal kinase (JNK), p38, and p50 in TGF-β1-induced NPDFs, but did not inhibit phosphorylation of extracellular signal-related kinase (ERK).. ATRA downregulated myofibroblast differentiation, ECM production, cell migration, and collagen gel contraction via p38, JNK-dependent NF-κB-signaling pathways in TGF-β1-induced NPDFs. The findings suggest that ATRA could serve as a novel therapeutic agent to ameliorate nasal polyp development.

Topics: Cell Differentiation; Cell Movement; Cells, Cultured; Collagen; Extracellular Matrix; Fibroblasts; Humans; MAP Kinase Signaling System; Nasal Polyps; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Proto-Oncogene Proteins c-jun; Transforming Growth Factor beta1; Tretinoin

To acquire basic information concerning the function of the membrane-bound mucin MUC16 in nasal mucosa compared with the best-characterized membrane-bound mucin, MUC4.. In vitro study using semiquantatitive reverse transcription-polymerase chain reaction analysis and immunoassay.. Yeungnam University College of Medicine.. We examined the nasal polyps obtained during endoscopic sinus surgery in 10 patients, the normal ethmoid sinus mucosa obtained from 10 patients, and human nasal polyp epithelial (HNPE) cells.. Gene expression of MUC4 and MUC16 in nasal polyps and normal nasal mucosa. In addition, we evaluated the effect of 4 physiologically relevant agents, including retinoic acid, interleukin 1beta, phorbol 12-myristate 13-acetate (PMA), and dexamethasone, on the expression of MUC4 and MUC16 in HNPE cells at the gene and protein levels.. In nasal polyps, MUC4 was upregulated compared with normal nasal mucosa (P = .009), whereas MUC16 expression did not differ between nasal polyps and normal nasal mucosa. Retinoic acid and interleukin 1beta increased MUC4 expression at the gene and protein level in HNPE cells, whereas MUC16 expression was not affected. Unlike retinoic acid and interleukin 1beta, PMA and dexamethasone increased MUC16 expression, whereas they had no significant effect on MUC4 expression.. Expression of MUC4 and MUC16 are regulated differently in nasal mucosa. Dexamethasone and PMA are potent mediators for the expression of MUC16 in nasal polyps.

Topics: Adult; CA-125 Antigen; Cells, Cultured; Dexamethasone; Female; Gene Expression; Humans; Immunoassay; Interleukin-1beta; Male; Membrane Proteins; Mucin-4; Nasal Mucosa; Nasal Polyps; Reverse Transcriptase Polymerase Chain Reaction; Tetradecanoylphorbol Acetate; Tretinoin

To elucidate a mechanism of proliferation and differentiation of nasal gland cells, we established a serum-free 3-dimensional culture system for human nasal gland (HNG) cells and examined the effects of epidermal growth factor, keratinocyte growth factor, and retinoic acid on proliferation and differentiation of cultured HNG cells.. Nasal polyps were obtained from patients undergoing endoscopic endonasal sinus surgery. The HNG cells were cultured under a monolayer culture and transferred to a collagen-embedded culture using RPMI 1640 medium containing transferrin, insulin, hydrocortisone, retinoic acid, epidermal growth factor, and keratinocyte growth factor. Cell growth was measured by bromodeoxyuridine incorporation assays. To measure cell differentiation, the percentage of cells containing secretory granules, which were stained with Alcian blue in cytoplasm, was determined.. In the serum-free 3-dimensional culture, the HNG cells showed ductal structures containing secretory products in a lumen. The addition of epidermal growth factor promoted the proliferation of HNG cells in its optimal concentrations, and keratinocyte growth factor also enhanced the proliferation of HNG cells. Conversely, the differentiation of HNG cells was not dependent on epidermal growth factor and keratinocyte growth factor. Retinoic acid suppressed the proliferation, but promoted the differentiation of HNG cells.. Our culture system could be useful for studying the effects of various growth factors and cytokines on HNG proliferation and differentiation to better understand the mechanisms of growth and morphogenesis of nasal glands.

Topics: Cells, Cultured; Epidermal Growth Factor; Fibroblast Growth Factor 7; Fibroblast Growth Factors; Humans; In Vitro Techniques; Nasal Mucosa; Nasal Polyps; Tretinoin