Rafael Firszt

Interleukin-13 induces collagen type-1 expression through matrix metalloproteinase-2 and transforming growth factor-β1 in airway fibroblasts in asthma.

Airway remodelling is a feature of asthma that contributes to loss of lung function. One of the central components of airway remodelling is subepithelial fibrosis. Interleukin (IL)-13 is a key T-helper 2 cytokine and is believed to be the central mediator of allergic asthma including remodelling, but the mechanism driving the latter has not been elucidated in human asthma. We hypothesised that IL-13 stimulates collagen type-1 production by the airway fibroblast in a matrix metalloproteinase (MMP)- and transforming growth factor (TGF)-&bgr;1-dependent manner in human asthma as compared to healthy controls. Fibroblasts were cultured from endobronchial biopsies in 14 subjects with mild asthma and 13 normal controls that underwent bronchoscopy. Airway fibroblasts were treated with various mediators including IL-13 and specific MMP-inhibitors. IL-13 significantly stimulated collagen type-1 production in asthma compared to normal controls. Inhibitors of MMP-2 significantly attenuated collagen production in asthma but had no effect in normal controls. IL-13 significantly increased total and active forms of TGF-&bgr;1, and this activation was blocked using an MMP-2 inhibitor. IL-13 activated endogenous MMP-2 in asthma patients as compared to normal controls. In an ex vivo model, IL-13 potentiates airway remodelling through a mechanism involving TGF-&bgr;1 and MMP-2. These effects provide insights into the mechanism involved in IL-13-directed airway remodelling in asthma. IL-13 potentiates collagen production in a TGF-&bgr;1-dependent manner providing insight into airway remodelling in asthma http://ow.ly/r5v7s

Airway fibroblasts in asthma manifest an invasive phenotype.

RATIONALE Invasive cell phenotypes have been demonstrated in malignant transformation, but not in other diseases, such as asthma. Cellular invasiveness is thought to be mediated by transforming growth factor (TGF)-β1 and matrix metalloproteinases (MMPs). IL-13 is a key T(H)2 cytokine that directs many features of airway remodeling through TGF-β1 and MMPs. OBJECTIVES We hypothesized that, in human asthma, IL-13 stimulates increased airway fibroblast invasiveness via TGF-β1 and MMPs in asthma compared with normal controls. METHODS Fibroblasts were cultured from endobronchial biopsies in 20 subjects with mild asthma (FEV(1): 90 ± 3.6% pred) and 17 normal control subjects (FEV(1): 102 ± 2.9% pred) who underwent bronchoscopy. Airway fibroblast invasiveness was investigated using Matrigel chambers. IL-13 or IL-13 with TGF-β1 neutralizing antibody or pan-MMP inhibitor (GM6001) was added to the lower chamber as a chemoattractant. Flow cytometry and immunohistochemistry were performed in a subset of subjects to evaluate IL-13 receptor levels. MEASUREMENTS AND MAIN RESULTS IL-13 significantly stimulated invasion in asthmatic airway fibroblasts, compared with normal control subjects. Inhibitors of both TGF-β1 and MMPs blocked IL-13-induced invasion in asthma, but had no effect in normal control subjects. At baseline, in airway tissue, IL-13 receptors were expressed in significantly higher levels in asthma, compared with normal control subjects. In airway fibroblasts, baseline IL-13Rα2 was reduced in asthma compared with normal control subjects. CONCLUSIONS IL-13 potentiates airway fibroblast invasion through a mechanism involving TGF-β1 and MMPs. IL-13 receptor subunits are differentially expressed in asthma. These effects may result in IL-13-directed airway remodeling in asthma.

Risk of Autoimmunity in EoE and Families: A Population-Based Cohort Study.

Objectives:Recent genome-wide association studies have suggested possible genetic associations between eosinophilic esophagitis (EoE) and genes associated with autoimmunity. No studies to date have looked at potential genetic association of EoE with specific autoimmune diseases by evaluating such diagnoses within family members. Investigate the risk of specific autoimmune disease within EoE probands and their extended family members.Methods:The Utah Population Database offers a unique opportunity to link medical records from over 85% of Utah’s population to genealogy records representing Utah. We searched for associations of specific autoimmune diseases in probands diagnosed with EoE and their extended family members (e.g., first cousins). Comparisons were made to age- and sex-matched controls and their respective families at a 5:1 ratio.Results:Excess risk for multiple autoimmune conditions was detected in subjects with a diagnosis of EoE. Celiac, Crohn’s, ulcerative colitis (UC), rheumatoid arthritis, IgA deficiency, CVID, multiple sclerosis (MS), and Hashimoto’s thyroiditis were found at increased risk in first-degree relatives of EoE subjects. UC, systemic sclerosis, and MS had nominally significant associations within second-degree family members of EoE subjects; and, in reverse analysis, probands and their families with the above three conditions were at an increased risk for EoE suggesting shared genetic factors with EoE.Conclusions:Patients with EoE have an increased risk of multiple autoimmune diseases. Possible shared genetic etiologies were observed between EoE and UC, systemic sclerosis, and MS. Practitioners should be aware of these comorbid associations and query all EoE patients and family members for symptoms of these diseases.

Pharmacotherapy of severe asthma.

Severe asthma is a complex and heterogeneous phenotype where management can be challenging. While many patients with severe asthma respond to high-dose inhaled corticosteroids in combination with a long-acting beta-agonist, there remains a significant subset of patients that require oral corticosteroids to control symptoms. Alternative therapies are needed to help reduce the need for continuous oral corticosteroids; however, there are currently very few effective options. Several new alternatives to oral corticosteroids have been evaluated in severe asthma as add-on to conventional therapy. These include macrolide antibiotics, omalizumab, tumor necrosis factor-alpha inhibitors, cytokine receptor antagonists, and bronchial thermoplasty. The challenge with these entities is determining the appropriate phenotype of severe asthma where effectiveness is demonstrated, given the significant heterogeneity of the disease. Therefore, there is a crucial need to better understand the mechanisms and pathophysiology of severe asthma so more effective immunomodulators and biologic therapies can emerge.

An overview of novel therapies for acute hereditary angioedema.

Hereditary angioedema is an episodic swelling disorder with autosomal dominant inheritance. Attacks are characterized by nonpitting edema of external or mucosal body surfaces. Patients often present with swelling of the extremities, abdominal pain, and swelling of the mouth and throat, which can at times lead to asphyxiation. The disease is caused by a mutation in the gene encoding the complement C1-inhibitor protein, which leads to unregulated production of bradykinin.Long-term therapy has depended on the use of attenuated androgens or plasmin inhibitors but in the US there was, until recently, no specific therapy for acute attacks. As well, many patients with hereditary angioedema in the US were either not adequately controlled on previously available therapies or required doses of medications that exposed them to the risk of serious adverse effects. Five companies have completed or are currently conducting phase III clinical trials in the development of specific therapies to terminate acute attacks or to be used as prophylaxis. These products are based on either replacement therapy with purified plasma-derived or recombinant C1-inhibitor, or inhibition of the kinin-generating pathways with a recombinant plasma kallikrein inhibitor or bradykinin type 2 receptor antagonist. Published studies thus far suggest that all of these products are likely to be effective. These new therapies will likely lead to a totally new approach in treating hereditary angioedema.

Transfer of peanut IgE sensitisation after combined pancreas–kidney transplant

The transfer of peanut allergy has been reported following solid organ transplantation.

Successful treatment of idiopathic angioedema with ecallantide

TO THE EDITOR: We present the case of a 16-year-old girl with recurrent episodes of facial angioedema and severe abdominal pain. The patient developed recurrent swelling of her eyelids, tongue, and face without associated urticaria. She had severe abdominal pain and diarrhea during these attacks. On average, these episodes occurred once or twice a month and lasted for 72 hours without treatment. She had no history of allergies. She did not use nonsteroidal anti-inflammatory drugs, oral contraceptive pills, or angiotensin-converting enzyme inhibitors. She had no family history of angioedema. The patient underwent a diagnostic evaluation to exclude hereditary angioedema (HAE), acquired angioedema, or other causes of her facial swelling. Her physical examination was pertinent for absence of lymphadenopathy, enlarged salivary glands, urticarial lesions, or urticaria pigmentosa. Her laboratory values consisted of normal leukocyte and eosinophil counts, normal thyroid-stimulating hormone, and negative antinuclear antibody. She had normal IgE levels. On the basis of skin and in vitro allergy testing, she had no sensitivity to indoor or outdoor allergens. Tryptase levels at baseline and during an acute attack were normal. She had normal results of a urinalysis collected during an acute attack. Because of the primary involvement of her head and neck, a computed tomographic chest scan was obtained to rule out superior vena cava syndrome. Results of the imaging study were normal. The patient was also evaluated for HAE, characterized by abnormalities in the level or function of C1-inhibitor protein (C1-INH). She had no evidence of HAE type I, with a C1-INH level of 37 mg/dL at baseline and 39 mg/dL during an acute attack. In addition, she did not have HAE type II, with a C1-INH functional percentage of 118% at baseline and 127% during an attack. Her C4 level was 33 mg/dL at baseline and 38 mg/dL during an attack (Table I). Gene testing for factor XII mutation was negative. To prevent attacks, the patient tried high-dose antihistamines, including fexofenadine 180 mg daily, hydroxyzine 100 mg daily, diphenhydramine 50 mg 4 times a day, and cetirizine 10 mg daily. Despite antihistamine therapy, she continued to have frequent attacks, suggesting she had nonhistaminergic angioedema. In an attempt to prevent attacks, she tried danazol 200 mg twice daily for 4 weeks, and Depo-Provera injections, without benefit. Because of the severity of her attacks, she required frequent hospitalization and received numerous courses of epinephrine, steroids, and diphenhydramine. None of these therapies were effective in resolving or shortening the duration of her symptoms. During an attack, she presented to our emergency department with acute facial swelling and severe abdominal pain. Because of her previous lack of response to other medications, we elected to treat her with ecallantide (total dose of 30 mg). Interestingly, her symptoms began to improve within 30 minutes and completely resolved within 4 hours. The patient was discharged from the emergency department later that evening. She has since received 9 ecallantide treatments for subsequent acute angioedema attacks. She continues to have symptom relief within 30 minutes of receiving ecallantide and complete resolution of her symptoms at 4 hours. Angioedema is characterized by swelling of the dermis, subcutaneous tissue, and mucous membranes. The swelling is generally asymmetric, nondependent, and non-pitting. If the larynx is involved, swelling of the head and neck can be life threatening. Treatment strategies focus on inhibiting various mediators of angioedema. Histamine, released by IgE, direct mast cell stimulation, or possibly other mechanisms, mediates angioedema and is prevented by antihistamine therapy. This is classified as histaminergic forms of angioedema. However, nonhistaminergic forms of angioedema may be mediated by bradykinin and refractory to antihistamine therapy. Nonhistaminergic angioedema includes HAE, with C1-INH deficiency or dysfunction (type I or type II, respectively), HAE type III (family history of angioedema and normal C1-INH), angiotensin-converting enzyme inhibitoreassociated angioedema, acquired angioedema, and idiopathic angioedema (IAE). Nonhistaminergic IAE is associated with normal C1-INH levels and function, lack of improvement with antihistamine therapy, and absence of a family history of angioedema. Patients with nonhistaminergic forms of angioedema often require alternative treatment strategies. Recently, several new products were approved in the US market that specifically and effectively treat HAE types I and II and acquired angioedema due to C1-INH deficiency, leading to a totally new approach in managing these

Management of acute attacks of hereditary angioedema: role of ecallantide

Hereditary angioedema (HAE) is characterized as an episodic swelling disorder with autosomal dominant inheritance. Clinical features include nonpitting edema of external or mucosal body surfaces, and patients often present with swelling of the extremities, abdominal pain, and swelling of the mouth and throat, which can lead to asphyxiation. Patients with HAE classically have no associated urticaria, which is often referred to as nonhistaminergic angioedema. Treatment for HAE involves long-term prophylaxis, short-term prophylaxis, and management of acute attacks. Up until the past few years, acute HAE episodes were predominately treated with supportive measures. Three classes of medications have recently been approved by the US Food and Drug Administration (FDA) for the management of acute HAE attacks. Ecallantide, a recombinant protein that acts as a reversible inhibitor of kallikrein, is currently indicated for acute attacks of HAE in those aged ≥12 years. In two randomized, double-blind, placebo-controlled, multicenter trials, EDEMA3 and EDEMA4, patients treated with 30 mg of ecallantide demonstrated statistically significant improvement in symptoms compared to those on placebo. In addition to its use as treatment for HAE, ecallantide has been used off label in the management of nonhistaminergic angioedema, not due to HAE. Ecallantide has shown promise in the treatment of these other forms; however, data are limited to mainly case reports at this time. Ecallantide is generally a safe and well-tolerated medication; however, based on reports of anaphylaxis, ecallantide does contain a black box warning. Due to the risk of anaphylaxis, ecallantide cannot be self-administered and must be given by a health care professional. Overall, ecallantide is a safe and effective medication for the treatment of acute attacks of HAE.

Role of Matrix Metalloproteinases-1 and -2 in Interleukin-13-Suppressed Elastin in Airway Fibroblasts in Asthma.

Elastin synthesis and degradation in the airway and lung parenchyma contribute to airway mechanics, including airway patency and elastic recoil. IL-13 mediates many features of asthma pathobiology, including airway remodeling, but the effects of IL-13 on elastin architecture in the airway wall are not known. We hypothesized that IL-13 modulates elastin expression in airway fibroblasts from subjects with allergic asthma. Twenty-five subjects with mild asthma (FEV1, 89 ± 3% predicted) and 30 normal control subjects (FEV1, 102 ± 2% predicted) underwent bronchoscopy with endobronchial biopsy. Elastic fibers were visualized in airway biopsy specimens using Weigerts resorcin-fuchsin elastic stain. Airway fibroblasts were exposed to IL-13; a pan-matrix metalloproteinase (MMP) inhibitor (GM6001); specific inhibitors to MMP-1, -2, -3, and -8; and combinations of IL-13 with MMP inhibitors in separate conditions in serum-free media for 48 hours. Elastin (ELN) expression as well as MMP secretion and activity were quantified. Results of this study show that elastic fiber staining of airway biopsy tissue was significantly associated with methacholine PC20 (i.e., the provocative concentration of methacholine resulting in a 20% fall in FEV1 levels) in patients with asthma. IL-13 significantly suppressed ELN expression in asthmatic airway fibroblasts as compared with normal control fibroblasts. The effect of IL-13 on ELN expression was significantly correlated with postbronchodilator FEV1/FVC in patients with asthma. MMP inhibition significantly stimulated ELN expression in patients with asthma as compared with normal control subjects. Specific inhibition of MMP-1 and MMP-2, but not MMP-3 or MMP-8, reversed the IL-13-induced suppression of ELN expression. In asthma, MMP-1 and MMP-2 mediate IL-13-induced suppression of ELN expression in airway fibroblasts.

Population-based familial aggregation of eosinophilic esophagitis suggests a genetic contribution

Background: Prior familial clustering studies have observed an increased risk of eosinophilic esophagitis (EoE) mostly among first‐degree relatives, suggesting a genetic contribution to EoE, and twin studies have suggested a powerful contribution from environmental factors. Objective: This study sought to clarify the contribution of genetic factors to EoE through estimation of familial aggregation and risk of EoE in extended relatives. Methods: The Utah Population Database, a population‐based genealogy resource linked to electronic medical records for health care systems across the state of Utah, was used to identify EoE cases and age, sex, and birthplace‐matched controls at a 5:1 ratio. Logistic regression was used to determine the odds of EoE among relatives of EoE probands compared with the odds of EoE among relatives of controls. Results: There were 4,423 EoE cases and 24,322 controls. The population‐attributable risk of EoE was 31% (95% CI, 28% to 34%), suggesting a relatively strong genetic contribution. Risks of EoE were significantly increased among first‐degree relatives (odds ratio [OR], 7.19; 95% CI, 5.65‐9.14), particularly first‐degree relatives of EoE cases diagnosed <18 years of age (OR, 16.3; 95% CI, 9.4‐28.3); second‐degree relatives (OR, 1.99; 95% CI, 1.49‐2.65); and first cousins (OR, 1.35; 95% CI, 1.03‐1.77), providing evidence of a genetic contribution. However, spouses of EoE probands were observed to be at increased risk of EoE (OR, 2.86; 95% CI, 1.31‐6.25), suggesting either positive assortative mating or a shared environmental contribution to EoE. Conclusions: This study supports a significant genetic contribution to EoE as evidenced by increased risk of EoE in distant relatives.