Effect of TGF-ß1 on eosinophils to induce cysteinyl leukotriene E4 production in aspirin-exacerbated respiratory disease.

Cysteinyl leukotriene (cysLT) overproduction and eosinophil activation are hallmarks of aspirin-exacerbated respiratory disease (AERD). However, pathogenic mechanisms of AERD remain to be clarified. Here, we aimed to find the significance of transforming growth factor beta 1 (TGF-ß1) in association with cysteinyl leukotriene E4 (LTE4) production, leading to eosinophil degranulation. To evaluate levels of serum TGF-ß1, first cohort enrolled AERD (n = 336), ATA (n = 442) patients and healthy control subjects (HCs, n = 253). In addition, second cohort recruited AERD (n = 34) and ATA (n = 25) patients to investigate a relation between levels of serum TGF-ß1 and urinary LTE4. The function of TGF-ß1 in LTE4 production was further demonstrated by ex vivo (human peripheral eosinophils) or in vivo (BALB/c mice) experiment. As a result, the levels of serum TGF-ß1 were significantly higher in AERD patients than in ATA patients or HCs (P = .001; respectively). Moreover, levels of serum TGF-ß1 and urinary LTE4 had a positive correlation (r = 0.273, P = .037). In the presence of TGF-ß1, leukotriene C4 synthase (LTC4S) expression was enhanced in peripheral eosinophils to produce LTE4, which sequentially induced eosinophil degranulation via the p38 pathway. When mice were treated with TGF-ß1, significantly induced eosinophilia with increased LTE4 production in the lung tissues were noted. These findings suggest that higher levels of TGF-ß1 in AERD patients may contribute to LTE4 production via enhancing LTC4S expression which induces eosinophil degranulation, accelerating airway inflammation.

Cellular interactions in aspirin-exacerbated respiratory disease.

PURPOSE OF REVIEW: The purpose of this review is to summarize the complex cellular interactions of aspirin-exacerbated respiratory disease (AERD) and how these interactions promote pathogenic mechanisms of AERD. RECENT FINDINGS: In addition to characteristic changes in eicosanoid levels, recent studies have identified increases in alarmin cytokines (IL-33, thymic stromal lymphopoietin) as well as activated innate lymphoid and plasma cell populations in samples from AERD patients. SUMMARY: Patients with AERD typically demonstrate high levels of proinflammatory eicosanoids including cysteinyl leukotrienes (CysLTs) and prostaglandin D2 (PGD2) and hyporesponsiveness to prostaglandin E2 (PGE2). CysLTs are released by mast cells, eosinophils, and adherent platelets and promote epithelial release of IL-33, which activates mast cells and group 2 innate lymphoid cells (ILC2s) in concert with CysLTs. TSLP induces PGD2 release from mast cells which activates and recruits eosinophils, basophils, Th2 cells, and ILC2s via CRTH2. In turn, ILC2s and other cell types produce Th2 cytokines IL-4, IL-5, and IL-13 that, along with CysLTs and PGD2, promote bronchoconstriction, eosinophilic tissue inflammation, and mucus production.

A proinflammatory marker in chronic rhinosinusitis: serum calprotectin.

INTRODUCTION: Studies have shown that calprotectin has a strong pro-inflammatory effect. Elevated calprotectin levels in the serum can be used as a strong clinical marker indicating the presence of inflammation. OBJECTIVE: To investigate serum calprotectin levels in patients with chronic rhinosinusitis (CRS) and to determine the applicability of calprotectin as a potential molecular pro-inflammatory biomarker for CRS. METHODS: The study consisted of three groups: chronic rhinosinusitis with polyps (CRSwNP group), chronic rhinosinusitis without polyps (CRSwoNP), and healthy control. CRS patients with polyps were further divided into two groups depending on the presence/absence of Samter's triad. The Nose Obstruction Symptom Evaluation (NOSE) scale score and serum calprotectin value were evaluated in all participants. RESULTS: The mean serum calprotectin value was 79.5±11.8 ng/ml for the CRSwNP group, 71.3±16 ng/ml for the CRSwoNP group, and 61.9±11.6 ng/ml for the control group (p<0.001). The Samter's triad group had a significantly higher calprotectin value than the non-Samter's triad group (p=0.03). There was a significant correlation between the NOSE scores and calprotectin levels (rho=0.734, p<0.001). CONCLUSION: Serum calprotectin values were correlated with the severity of symptoms in patients with CRS; thus, it seems to be a valuable pro-inflammatory biomarker for the diagnosis of the disease and determining its severity. Further studies with larger series are needed to evaluate the preoperative and postoperative serum calprotectin values ​​in patients undergoing surgery.

Serum level of stem cell factor and its soluble receptor in aspirin-exacerbated respiratory disease.

Aim: Stem cell factor (SCF) may be associated with inflammatory processes leading to aspirin-induced asthma. This study evaluated the relationship between serum level of SCF and its soluble receptor with aspirin-induced asthma. Methods & materials: Twenty-five patients and 25 healthy controls were enrolled in this study. The concentration of SCF and mast/stem cell growth factor receptor (C-kit) was determined in serum samples. Spirometry and rhinometry were performed to determine the severity of the disease. p < 0.05 were considered significant. Results: The serum levels of SCF and C-kit receptor were significantly higher in the case group. The serum SCF and C-kit level had a significant positive correlation with the severity of asthma, disease duration and nasal obstruction. Conclusion: Our findings suggest that SCF and C-kit receptors have a direct effect on the severity of aspirin-induced asthma.

Sinus Surgery Is Associated with a Decrease in Aspirin-Induced Reaction Severity in Patients with Aspirin Exacerbated Respiratory Disease.

BACKGROUND: Nasal polyps influence the burden of aspirin-exacerbated respiratory disease (AERD) by contributing to eicosanoid production. AERD is diagnosed through graded aspirin challenges. It is not known how sinus surgery affects aspirin challenge outcomes. OBJECTIVE: To investigate the effects of endoscopic sinus surgery (ESS) on aspirin-induced reaction severity and on the levels of eicosanoids associated with these reactions. METHODS: Twenty-eight patients with AERD were challenged with aspirin before and 3 to 4 weeks after ESS. Respiratory parameters and plasma and urine levels of eicosanoids were compared before and after challenges. RESULTS: Before ESS, AERD diagnosis was confirmed in all study patients by aspirin challenges that resulted in hypersensitivity reactions. After ESS, reactions to aspirin were less severe in all patients and 12 of 28 patients (43%, P < .001) had no detectable reaction. A lack of clinical reaction to aspirin was associated with lower peripheral blood eosinophilia (0.1 K/µL [interquartile range (IQR) 0.1-0.3] vs 0.4 K/µL [IQR 0.2-0.8]; P = .006), lower urinary leukotriene E4 levels after aspirin challenge (98 pg/mg creatinine [IQR 61-239] vs 459 pg/mg creatinine [IQR 141-1344]; P = .02), and lower plasma prostaglandin D2 to prostaglandin E2 ratio (0 [±0] vs 0.43 [±0.2]; P = .03), compared with those who reacted. CONCLUSIONS: Sinus surgery results in decreased aspirin sensitivity and a decrease in several plasma and urine eicosanoid levels in patients with AERD. Diagnostic aspirin challenges should be offered to patients with suspected AERD before ESS to increase diagnostic accuracy. Patients with established AERD could undergo aspirin desensitizations after ESS as the severity of their aspirin-induced hypersensitivity reactions lessens.

The utility of biomarkers in diagnosis of aspirin exacerbated respiratory disease.

BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is a distinct eosinophilic phenotype of severe asthma with accompanying chronic rhinosinusitis, nasal polyposis, and hypersensitivity to aspirin. Urinary 3-bromotyrosine (uBrTyr) is a noninvasive marker of eosinophil-catalyzed protein oxidation. The lack of in vitro diagnostic test makes the diagnosis of AERD difficult. We aimed to determine uBrTyr levels in patients with AERD (n = 240) and aspirin-tolerant asthma (ATA) (n = 226) and to assess whether its addition to urinary leukotriene E4 (uLTE4) levels and blood eosinophilia can improve the prediction of AERD diagnosis. METHODS: Clinical data, spirometry and blood eosinophilis were evaluated. UBrTyr and uLTE4 levels were measured in urine by HPLC and ELISA, respectively. RESULTS: Both groups of asthmatics (AERD, n = 240; ATA, n = 226) had significantly higher uBrTyr, uLTE4 levels, and blood eosinophils than healthy controls (HC) (n = 71) (p < 0.05). ULTE4 levels and blood eosinophils were significantly higher in AERD as compared to ATA (p = 0.004, p < 0.0001, respectively). whereas uBrTyr levels were not significantly different between both asthma phenotypes (p = 0.34). Asthmatics with high levels of uBrTyr (> 0.101 ng/mg Cr), uLTE4 levels (> 800 pg/mg Cr) and blood eosinophils (> 300 cells/ul) were 7 times more likely to have AERD.. However, uBrTyr did not increase the benefit for predicting AERD when uLTE4 and blood eosinophils were already taken into account (p = 0.57). CONCLUSION: UBrTyr levels are elevated both in AERD and ATA as compared to HC, but they could not differentiate between these asthma phenotypes suggesting a similar eosinophilic activation. The addition of uBrTyr to elevated uLTE4 levels and blood eosinophils did not statistically enhance the prediction of AERD diagnosis.

Dietary Fatty Acid Modification for the Treatment of Aspirin-Exacerbated Respiratory Disease: A Prospective Pilot Trial.

BACKGROUND: The high levels of eicosanoid production and the clinical efficacy of leukotriene-modifying pharmacotherapies for patients with aspirin-exacerbated respiratory disease (AERD) suggest that other interventions targeting arachidonic acid dysregulation may also improve disease control. OBJECTIVE: To assess the utility of a high omega-3/low omega-6 diet for the treatment of AERD. METHODS: Prospective, nonblinded dietary intervention in 10 adult patients with AERD at Brigham and Women's Hospital in Boston, MA. The primary objective was for subjects to reduce dietary omega-6 fatty acid consumption to less than 4 g/d and increase omega-3 intake to more than 3 g/d. The primary outcome was change in urinary leukotriene E4, with changes in other eicosanoids, platelet activation, lung function, and patient-reported questionnaires also assessed. RESULTS: Of the 10 subjects who screened for the study, all 10 completed the dietary intervention. Urinary leukotriene E4 decreased by 0.17 ng/mg (95% CI, -0.29 to -0.04; P = .02) and tetranor prostaglandin D-M decreased by 0.66 ng/mg creatinine (95% CI, -1.21 to -0.11; P = .02). There was a 15.1-point reduction in the 22-item Sino-Nasal Outcome Test score (95% CI, -24.3 to -6.0; P = .01), a 0.27-point reduction in the 7-item Asthma Control Questionnaire score (95% CI, -0.52 to -0.03; P = .03), and no change in FEV1 % predicted (P = .92) or forced vital capacity % predicted (P = .74). All patients lost some weight over the 2-week intervention period, and there were no diet-associated adverse events. CONCLUSIONS: A high omega-3/low omega-6 diet may be an appropriate adjunct treatment option for patients with AERD.

Potential Biomarkers for NSAID-Exacerbated Respiratory Disease.

Asthma is a common chronic disease with several variant phenotypes and endotypes. NSAID-exacerbated respiratory disease (NERD) is one such endotype characterized by asthma, chronic rhinosinusitis (CRS) with nasal polyps, and hypersensitivity to aspirin/cyclooxygenase-1 inhibitors. NERD is more associated with severe asthma than other asthma phenotypes. Regarding diagnosis, aspirin challenge tests via the oral or bronchial route are a standard diagnostic method; reliable in vitro diagnostic tests are not available. Recent studies have reported various biomarkers of phenotype, diagnosis, and prognosis. In this review, we summarized the known potential biomarkers of NERD that are distinct from those of aspirin-tolerant asthma. We also provided an overview of the different NERD subgroups.

Association of interleukin-25 levels with development of aspirin induced respiratory diseases.

BACKGROUND: Aspirin-exacerbated respiratory diseases (AERD) are caused by ingestion of non-steroidal anti-inflammatory drugs and are characterized by acute bronchospasms and marked infiltration of eosinophils, the latter being attributable to altered synthesis of cysteinyl leukotrienes (LT) and prostaglandins (PG). Recently, the innate Th2 response is revealed to induce eosinophil infiltration in allergic inflammation, however the role of the innate Th2 response has not been studies in AERD. Thus, we evaluated the relationship between the innate Th2 cytokines including IL-25, thymic stromal lymphopoietin (TSLP) and IL-33 and the development of AERD. METHODS AND MATERIALS: Plasma IL-25, IL-33, and TSLP levels were measured before and after aspirin challenge in subjects with AERD (n = 25) and aspirin-tolerant asthma (ATA, n = 25) by enzyme-linked immunosorbent assay (ELISA). Pre and post-aspirin challenge levels of LTC4 and PGD2 were measured using ELISA. RESULTS: Basal plasma IL-25 levels were significantly higher in AERD group than in normal controls and in ATA group (p = 0.025 and 0.031, respectively). IL-33 and TSLP levels were comparable in the AERD and ATA groups. After the aspirin challenge, the IL-25 levels were markedly decreased in the ATA group (p = 0.024), while not changed in the AERD group. The post-challenge IL-25 levels of all asthmatic subjects were significantly correlated with aspirin challenge - induced declines in FEV1 (r = 0.357, p = 0.011), but not with basal and post challenge LTC4 and PGD2 levels. CONCLUSIONS: IL-25 is associated with bronchospasm after aspirin challenge, possibly via mechanisms other than altered LTC4 and PGD2 production.

Thymic stromal lymphopoietin controls prostaglandin D2 generation in patients with aspirin-exacerbated respiratory disease.

BACKGROUND: Prostaglandin (PG) D2 is the dominant COX product of mast cells and is an effector of aspirin-induced respiratory reactions in patients with aspirin-exacerbated respiratory disease (AERD). OBJECTIVE: We evaluated the role of the innate cytokine thymic stromal lymphopoietin (TSLP) acting on mast cells to generate PGD2 and facilitate tissue eosinophilia and nasal polyposis in patients with AERD. METHODS: Urinary eicosanoid levels were measured in aspirin-tolerant control subjects and patients with AERD. Nasal polyp specimens from patients with AERD and chronic rhinosinusitis were analyzed by using quantitative PCR, Western blotting, and immunohistochemistry. Human cord blood-and peripheral blood-derived mast cells were stimulated with TSLP in vitro to assess PGD2 generation. RESULTS: Urinary levels of a stable PGD2 metabolite (uPGD-M) were 2-fold higher in patients with AERD relative to those in control subjects and increased further during aspirin-induced reactions. Peak uPGD-M levels during aspirin reactions correlated with reductions in blood eosinophil counts and lung function and increases in nasal congestion. Mast cells sorted from nasal polyps expressed PGD2 synthase (hematopoietic PGD2 synthase) mRNA at higher levels than did eosinophils from the same tissue. Whole nasal polyp TSLP mRNA expression correlated strongly with mRNA encoding hematopoietic PGD2 synthase (r = .75), the mast cell-specific marker carboxypeptidase A3 (r = .74), and uPGD-M (r = 0.74). Levels of the cleaved active form of TSLP were increased in nasal polyps from patients with AERD relative to those in aspirin-tolerant control subjects. Recombinant TSLP induced PGD2 generation by cultured human mast cells. CONCLUSIONS: Our study demonstrates that mast cell-derived PGD2 is a major effector of type 2 immune responses driven by TSLP and suggests that dysregulation of this innate system contributes significantly to the pathophysiology of AERD.