Cysteinyl leukotriene expression in chronic hyperplastic sinusitis–nasal polyposis: Importance to eosinophilia and asthma

doi:10.1067/mai.2003.67

Journal of Allergy and Clinical Immunology

Volume 111, Issue 2, February 2003, Pages 342-349

https://doi.org/10.1067/mai.2003.67 Get rights and content

Abstract

Background: Chronic hyperplastic eosinophilic sinusitis (CHS) results from the unregulated proliferation of eosinophils, T_H2-like lymphocytes, goblet cells, mast cells, and fibroblasts and is present in most patients with asthma. The frequent coexpression of these disorders and their shared pathophysiology suggests that these are similar disorders affecting the upper and lower airways. Objective: We evaluated the expression of cysteinyl leukotrienes (CysLTs) in sinus tissue from subjects with CHS compared with that seen in healthy sinus tissue. Methods: Nasal polyp and sinus tissue was evaluated from 58 individuals undergoing elective functional endoscopic sinus surgery. The diagnosis of CHS was demonstrated through the presence of eosinophilia and activated (EG2⁺) eosinophils, as determined by means of tissue immunohistochemistry. Data were compared with those from both nasal polyp tissue without eosinophilic inflammation and healthy control sinus tissue obtained from the sinus ostiomeatal complex at the time of surgery for unrelated disorders. CysLTs were quantified by means of ELISA in lipid-extracted tissue. Activation of the metabolic pathway leading to CysLT synthesis was demonstrated by ribonuclease protection. Subjects were genotyped for leukotriene C₄ (LTC₄) synthase C-to-A promoter polymorphism. Results: CysLT concentrations were significantly higher in tissue obtained from subjects with CHS (776.7 ± 201.9 pg/g tissue) compared with that seen in healthy sinus tissue (355.7 ± 101.6 pg/g tissue, P < .03). CysLT concentrations within noneosinophilic nasal polyps (328.0 ± 116.4 pg/g tissue) were similar to those in control tissue. The presence of CysLTs in CHS was associated with increased expression of LTC₄ synthase mRNA. The C-to-A promoter polymorphism was associated with trends toward the increased presence of CHS and CysLTs. Conclusions: CHS is characterized by the increased presence of CysLTs when compared with concentrations seen in tissue from patients with chronic inflammatory sinusitis or healthy sinus tissue. These studies support the use of LT modifiers as anti-inflammatory agents that might have clinical benefit in patients with these disorders. (J Allergy Clin Immunol 2003;111:342-9.)

Section snippets

Subjects

Polyp tissue was obtained from subjects (n = 58) referred to the University of Virginia Health System for sinus surgery. Subjects were asked their permission, and informed consent was given to study pathologic specimens under a protocol approved by the human investigations committee at the University of Virginia Health System. No individual was studied unless he or she had been recommended for and agreed to undergo sinus surgery. Study subjects were selected solely on the basis of a medical

Pathology

Only one subject had numerous neutrophils identified in polyp tissue, and this individual was excluded from further analyses. Microscopic examination of the polyp tissue in the remaining 57 subjects was characterized by a nonspecific mononuclear cell inflammatory infiltrate. Thirty-two pathologic specimens on blinded examination of multiple high-powered fields were identified as having “several” or “numerous” tissue eosinophils and were therefore considered to represent CHS. Tissue

Discussion

These studies compared the expression of CysLTs and metabolic pathways involved in CysLT synthesis between tissue from patients with CHS, noneosinophilic inflammation, or uninvolved healthy sinuses. The pathology and immunology of CHS share many features with asthma, and these conditions are frequently coincidentally expressed in patients.5, 6, 7 We therefore reasoned that these similarities would extend toward a tendency to express CysLTs. Subjects with CHS were defined by the presence of

References (43)

MA Kaliner et al.
Sinusitis: bench to bedside
J Allergy Clin Immunol
(1997)
SL Harlin et al.
A clinical and pathologic study of chronic sinusitis: The role of the eosinophil
J Allergy Clin Immunol
(1988)
P Demoly et al.
Assessment of inflammation in noninfectious chronic maxillary sinusitis
J Allergy Clin Immunol
(1994)
M Bresciani et al.
Rhinosinusitis in severe asthma
J Allergy Clin Immunol
(2001)
R Pfister et al.
Screening for sinus disease in patients with asthma: a computed tomography-controlled comparison of A-mode ultrasonography and standard radiography
J Allergy Clin Immunol
(1994)
DL Hamilos et al.
Evidence for distinct cytokine expression in allergic versus nonallergic chronic sinusitis
J Allergy Clin Immunol
(1995)
C Bachert et al.
IL-5 synthesis is upregulated in human nasal polyp tissue
J Allergy Clin Immunol
(1997)
PF Weller
Human eosinophils
J Allergy Clin Immunol
(1997)
F Lavigne et al.
Prognosis and prediction of response to surgery in allergic patients with chronic sinusitis
J Allergy Clin Immunol
(2000)
ER Wald
Microbiology of acute and chronic sinusitis in children and adults
Am J Med Sci
(1998)

L Borish

Sinusitis and asthma: entering the realm of scientific study

J Allergy Clin Immunol

(2002)

Cited by (144)

Innate immune cell dysregulation drives inflammation and disease in aspirin-exacerbated respiratory disease
2021, Journal of Allergy and Clinical Immunology
Citation Excerpt :
The constitutive overproduction of CysLTs in the resting state and the surge in CysLT production in response to nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) is pathognomonic for AERD.43,45 These elevated levels of CysLT in AERD reflect the increased expression of 5-lipoxygenase and leukotriene C4 synthase in inflammatory cells including MCs, with, as previously noted, additional contributions from eosinophils and basophils.46 Although these enzymes are expressed in several cell types, the elevation of other MC activation products, including tryptase, histamine, and PGD2, as well as the surge of PGD2 and tryptase on NSAID challenge, suggests an important role for MCs.47
Aspirin-exacerbated respiratory disease (AERD) is a complex inflammatory disorder that is not generally viewed as a disease involving the adaptive immune system but instead one largely driven by the innate immune system. This article focuses on the cellular dysregulation involving 4 central cell types: eosinophils, basophils, mast cells, and innate lymphoid type 2 cells. AERD can be envisioned as involving a self-perpetuating vicious circle in which mediators produced by a differentiated activated epithelial layer, such as IL-25, IL-33, and thymic stromal lymphopoietin, engage and activate each of these innate immune cells. The activation of these innate immune cells with their production of additional cytokine/chemokine and lipid mediators leads to further recruitment and activation of these innate immune cells. More importantly, numerous mediators produced by these innate immune cells provoke the epithelium to induce further inflammation. This self-perpetuating cycle of inflammation partially explains both current interventions suggested to ameliorate AERD (eg, aspirin desensitization, leukotriene modifiers, anti–IL-5/IL-5 receptor, anti–IL-4 receptor, and anti-IgE) and invites exploration of novel targets as specific therapies for this condition (prostaglandin D₂ antagonists or cytokine antagonists [IL-25, IL-33, thymic stromal lymphopoietin]). Several of these interventions currently show promise in small retrospective analyses but now require definite clinical trials.
Roles of innate lymphoid cells (ILCs) in allergic diseases: The 10-year anniversary for ILC2s
2021, Journal of Allergy and Clinical Immunology
In the 12 years since the discovery of innate lymphoid cells (ILCs), our knowledge of their immunobiology has expanded rapidly. Group 2 ILCs (ILC2s) respond rapidly to allergen exposure and environmental insults in mucosal organs, producing type 2 cytokines. Early studies showed that epithelium-derived cytokines activate ILC2s, resulting in eosinophilia, mucus hypersecretion, and remodeling of mucosal tissues. We now know that ILC2s are regulated by other cytokines, eicosanoids, and neuropeptides as well, and interact with both immune and stromal cells. Furthermore, ILC2s exhibit plasticity by adjusting their functions depending on their tissue environment and may consist of several heterogeneous subpopulations. Clinical studies show that ILC2s are involved in asthma, allergic rhinitis, chronic rhinosinusitis, food allergy, and eosinophilic esophagitis. However, much remains unknown about the immunologic mechanisms involved. Beneficial functions of ILCs in maintenance or restoration of tissue well-being and human health also need to be clarified. As our understanding of the crucial functions ILCs play in both homeostasis and disease pathology expands, we are poised to make tremendous strides in diagnostic and therapeutic options for patients with allergic diseases. This review summarizes discoveries in immunobiology of ILCs and their roles in allergic diseases in the past 5 years, discusses controversies and gaps in our knowledge, and suggests future research directions.
Effect of LTRA in L-ASA Challenge for Aspirin-Exacerbated Respiratory Disease Diagnosis
2021, Journal of Allergy and Clinical Immunology: In Practice
Aspirin-exacerbated respiratory disease (AERD) consists of asthma, chronic rhinosinusitis with polyps, and hypersensitivity to aspirin and/or nonsteroidal anti-inflammatory drugs (NSAIDs). Nasal Lysine Aspirin Challenge is an effective tool for the diagnosis of hypersensitivity to aspirin and/or NSAIDs in patients with AERD. However, there is no unified international consensus version to perform nasal provocation tests (NPTs).
To investigate the effect of a leukotriene receptor antagonist (LTRA), montelukast, on the lysine-acetylsalicylate (L-ASA) nasal challenge.
We included 86 patients divided into 3 samples: group A (AERD without LTRA), group B (AERD with LTRA), and the control group (NSAID-tolerant asthmatics). NPT with L-ASA was performed with 25 mg of L-ASA every 30 minutes 4 times followed by rhinomanometry and spirometric measurements and evaluation of symptoms using a novel clinical scale.
In group A, 94.5% of patients (35 of 37) developed a positive response to NPT (drop >40% in total nasal flow), whereas only 46% of group B subjects (13 of 28) showed a positive response to the nasal challenge (P < .001). Control subjects did not show any response to the L-ASA challenge. A novel clinical score demonstrated accuracy in classifying the hypersensitivity to aspirin and/or NSAIDs when patients avoid LTRA (33 of 37).
Patients with AERD without LTRA showed a greater positive response to the L-ASA challenge than those taking this drug; therefore, LTRA treatment should be discontinued before the challenge for optimal diagnostic accuracy.
Altered tissue specialized pro-resolving mediators in chronic rhinosinusitis
2021, Prostaglandins Leukotrienes and Essential Fatty Acids
Current literature implicates arachidonic acid-derived leukotrienes and prostaglandins in the pathogenesis of chronic rhinosinusitis. However, other omega-3 and omega-6 derived lipid mediators, such as specialized pro-resolving mediators (SPMs), may also be important in chronic inflammatory disorders of the upper airway. We hypothesize that SPMs differ among CRS subtypes compared to controls and in relation to sinonasal microbiota. Ethmoid sinus tissue and middle meatal swabs were collected from a convenience sample of 66 subjects, including non-CRS controls, CRS with polyps (CRSwNP), and CRS without polyps (CRSsNP). Lipid mediator pathways were analyzed by liquid chromatography/tandem mass spectrometry. Bacterial taxa were profiled in parallel by 16S rRNA gene sequencing. Resolvin D2 was elevated in both CRSwNP (p = 0.00076) and CRSsNP (p = 0.030) compared with non-CRS controls. Lipoxin A₄ was significantly increased in CRSwNP compared with CRSsNP (p = 0.000033) and controls (p = 0.044). Cigarette smoking was associated with significantly lower concentrations of several 15-lipoxygenase metabolites including resolvin D1 (p = 0.0091) and resolvin D2 (p = 0.0097), compared with never-smokers. Several of the lipid compounds also correlated with components of the sinonasal mucosal microbiota, including bacterial pathogens such as Pseudomonas aeruginosa. These data suggest that dysfunctional lipid mediator pathways in CRS extend beyond the traditional descriptions of leukotrienes and prostaglandins and include SPMs. Furthermore, dysregulated SPM signaling may contribute to persistent inflammation and bacterial colonization in CRS.
Systematic review of outcomes for endoscopic sinus surgery and subsequent aspirin desensitization in aspirin-exacerbated respiratory disease
2020, World Journal of Otorhinolaryngology - Head and Neck Surgery
To review and evaluate outcomes of patients with aspirin-exacerbated respiratory disease (AERD) following endoscopic sinus surgery and subsequent aspirin desensitization.
Electronic searches of OVID MEDLINE (1948 to September 10, 2019), EMBASE (1980 to September 10, 2019), and PubMed were performed on September 10, 2019. A systematic review of the literature was performed using the 2009 PRISMA guidelines. Studies with both preoperative and postoperative data for patients with AERD who underwent sinus surgery and aspirin desensitization were considered appropriate for inclusion. Publications were written in English and included patients aged 18 years or older.
Six studies met inclusion criteria for this systematic review. The primary outcome measure was change in symptom profile measured by patient-reported quality of life scores. The results demonstrate statistically significant improvement in symptoms following endoscopic sinus surgery, with sustained improvement following aspirin desensitization. Revision surgery rates were significantly lower in patients maintained on aspirin therapy.
This review suggests that surgery followed by aspirin desensitization results in improvement in both subjective and objective outcome measures. The adjunctive use of aspirin desensitization allows for long-term stability in symptom scores. Recurrence of polyps and worsening symptoms requiring revision surgery occurs when aspirin maintenance therapy is interrupted.
Aspirin exacerbated respiratory disease: Current topics and trends
2018, Respiratory Medicine
Aspirin-exacerbated respiratory disease is a chronic and treatment-resistant disease, characterized by the presence of eosinophilic rhinosinusitis, nasal polyposis, bronchial asthma, and nonsteroidal anti-inflammatory drugs hypersensitivity. Alterations in arachidonic acid metabolism may induce an imbalance between pro-inflammatory and anti-inflammatory substances, expressed as an overproduction of cysteinyl leukotrienes and an underproduction of prostaglandin E2. Although eosinophils play a key role, recent studies have shown the importance of other cells and molecules in the development of the disease like mast cells, basophils, lymphocytes, platelets, neutrophils, macrophages, epithelial respiratory cells, IL-33 and thymic stromal lymphopoietin, making each of them promissory diagnostic and treatment targets.
In this review, we summarize the most important clinical aspects of the disease, including the current topics about diagnosis and treatment, like provocation challenges and aspirin desensitization. We also discuss recent findings in the pathogenesis of the disease, as well as future trends in diagnosis and treatment, including monoclonal antibodies and a low salicylate diet as a treatment option.

View all citing articles on Scopus

^☆: Supported by National Institutes of Health grants AI01793 and AI/HL47737 and a medical school grant from Merck & Co, Inc.

^☆☆: Reprint requests: John W. Steinke, PhD, Asthma and Allergic Disease Center, Box 801355, University of Virginia Health System, Charlottesville, VA 22908.

View full text

Mechanisms of AllergyCysteinyl leukotriene expression in chronic hyperplastic sinusitis–nasal polyposis: Importance to eosinophilia and asthma☆,☆☆

Abstract

Section snippets

Subjects

Pathology

Discussion

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Am J Med Sci

Lancet

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Lancet

J Allergy Clin Immunol

Otolaryngol Head Neck Surg

Prostaglandins Leukot Essent Fatty Acids

Eosinophil infiltration in nonallergic chronic hyperplastic sinusitis with nasal polyposis (CHS/NP) is associated with endothelial VCAM-1 upregulation and expression of TNF-α

Am J Respir Cell Mol Biol

Nasal polyposis, eosinophil dominated inflammation, and allergy

Thorax

Sinusitis and asthma: entering the realm of scientific study

J Allergy Clin Immunol

Mechanisms of Allergy
Cysteinyl leukotriene expression in chronic hyperplastic sinusitis–nasal polyposis: Importance to eosinophilia and asthma☆,☆☆