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Biomedical subjects

Sally E Wenzel

Publications and source records attributed to Sally E Wenzel.

At least 19 recordsLinked to original sources
PubMed2026

Aberrant mucin expression and keratinization distinguishing severe from mild asthma revealed by interpretable machine learning.

Type 2 (T2) immune cells dominate the airways of patients with mild-moderate asthma (MMA) with a more complex type 1 (T1)-T2 mixed immune response evident in treatment-refractory severe asthma (SA). We hypothesized that comparing the transcriptomes of the airway epithelium of patients with SA and MMA would reveal molecular signatures associated with more severe disease in the context of a complex immune response. Using our interpretable machine learning tool, SLIDE, meaningful latent factors (context-specific gene co-expression networks) were revealed that distinguished SA from MMA. Unexpectedly, an aberrant high expression of normally host-protective, membrane-tethered, and IFN-inducible mucins, MUC1 and MUC4, was identified in SA. Gene networks in the significant latent factors discriminating SA from MMA corresponded to enrichment of a keratinization program in SA airways. Keratinization was marked by increased expression of the stress keratin KRT16, signifying squamous metaplasia suggesting adaptive reprogramming of the airway epithelium in response to chronic stress. These mucins and KRT16 were inversely associated with lung function in 2 separate asthma cohorts. Imaging of endobronchial biopsies revealed significantly higher KRT16 protein expression in SA compared with MMA that strongly correlated with MUC1 protein expression. Our study identifies dysregulated host-protective and maladaptive repair responses in SA distinguishing from MMA.

Humans↗
PubMed2026

A cross-sectional study of oxidative stress pathway genotypes and their interactions with environmental pollutant levels identifies associations with gene expression and lung function.

BACKGROUND: Asthma is a heterogeneous disease influenced by genetic and environmental factors. Fine particulate matter (PM2.5) exacerbates asthma, likely through oxidative stress pathways, but whether genetic variation modifies this effect remains unclear. METHODS: We analysed data on 948 adults with asthma from the Severe Asthma Research Program (SARP), linking ZIP-code-level PM2.5 exposure with whole-genome sequencing data. We tested 4337 single nucleotide polymorphisms (SNPs) in 120 oxidative stress pathway genes for gene-environment (GxE) interactions with PM2.5 on lung function (forced expiratory volume in 1 s [FEV1] % predicted) using weighted linear regression. Gene expression data from bronchial epithelial cells (n = 170) were used to assess cis-expression quantitative trait loci (eQTLs). FINDINGS: Higher PM2.5 exposure was associated with lower FEV1% predicted (β per μg/m3 = -0.7, p = 0.01). We identified 20 SNPs across seven genes (OXSR1, PXDN, TPO, LRRK2, APP, MSRA, MSRB2) with significant GxE interactions after multiple-testing correction. Five SNPs were also eQTLs, linking PM2.5-modified gene expression to lung function. Minor alleles in OXSR1 and PXDN were associated with reduced gene expression and worsened FEV1% under high PM2.5 exposure. Conversely, TPO variants were associated with higher baseline expression and lower lung function, but under increasing PM2.5 exposure, minor allele carriers showed suppressed TPO expression and improved FEV1%. INTERPRETATION: This study identified 20 SNPs in oxidative stress pathway genes that modify the effect of PM2.5 on lung function in asthma. These findings highlight the importance of integrating environmental context in genetic studies and suggest potential therapeutic targets for pollution-sensitive asthma phenotypes. FUNDING: Supported by NIH grants.

Cross-Sectional Studies↗
PubMed2025

α1-Antitrypsin Gene Variation Associates With Asthma Exacerbations and Related Health Care Utilization.

BACKGROUND: α1-Antitrypsin deficiency is caused by rare pathogenic variants in SERPINA1, the strongest genetic risk factor for chronic obstructive pulmonary disease. Few studies have evaluated the effects of SERPINA1 variation on asthma severity accounting for critical gene-by-environment interactions with smoking. OBJECTIVE: To characterize the influence of SERPINA1 variation on asthma severity. METHODS: DNA samples from 847 non-Hispanic White and 446 African American participants from the Severe Asthma Research Program underwent SERPINA1 resequencing to identify rare variants. An independent population of 1955 individuals with asthma and α1-antitrypsin concentrations from a Cleveland Clinic Health System (CCHS) database were evaluated for severity measures. RESULTS: In White participants, a history of minimum smoking significantly interacted with SERPINA1 low-to-rare frequency variation to determine risk for asthma-related health care utilization. This was attributed to protease inhibitor type Z heterozygotes (MZ, N = 11), who had a higher frequency of emergency department (ED) visits (6 [54.5%] MZ heterozygotes, odds ratio [OR] = 7.60, 95% confidence interval [CI] = 1.71-39.7, P = .010), hospitalization (5 [45.5%], OR = 16.1, 95% CI = 2.64-150.4, P = .0050) in the past year, and lifetime intensive care unit (ICU) admissions (6 [54.5%], OR = 12.5, 95% CI = 2.44-75.6, P = .0032) compared with 146 individuals without SERPINA1 variants (30 [20.5%] reporting ED visits, 17 [11.6%] hospitalization, and 15 [10.3%] ICU admission). SERPINA1 variant-by-ever smoking interactions in African American participants for ED visits (P = .069) were related to 4 of 6 compound heterozygotes reporting an ED visit. In CCHS, α1-antitrypsin concentrations were inversely associated with moderate-to-severe asthma risk (OR = 0.97 per 10 mg/dL increase in α1-antitrypsin, 95% CI = 0.94-0.99, P = .010) and exacerbations (OR = 0.84 per 10 mg/dL, 95% CI = 0.76-0.94, P = .002). CONCLUSIONS: SERPINA1 variation and α1-antitrypsin concentrations impact asthma severity through gene-environment interactions with minimum smoking.

Adult↗
PubMed2007

Severe asthma: lessons from the Severe Asthma Research Program.

Severe asthma affects only a small percentage of the asthma population. However, these patients remain poorly understood and difficult to treat. Because the numbers are relatively small (10% or less of the asthma population), a network approach with shared protocols, samples, and data provides a unique opportunity to recruit the numbers of subjects necessary to perform adequately powered studies. The Severe Asthma Network (Severe Asthma Research Program) was established by the National Heart, Lung, and Blood Institute in 2001 to advance collectively the study of severe asthma to determine factors that differentiated these patients or subjects from those with milder asthma. Nearly 800 subjects have been recruited in less than 4 years to begin to address these differences. Future studies will specifically evaluate the role of inflammatory/oxidative processes, infection, genetics, and the distal lung in the pathogenesis of severe asthma.

Asthma↗
PubMed2006

IL4R alpha mutations are associated with asthma exacerbations and mast cell/IgE expression.

BACKGROUND: Severe asthma has been associated with severe exacerbations, lower lung function and greater tissue inflammation. Previous studies have suggested that mutations in interleukin-4 receptor alpha (IL4Ralpha) are associated with lower lung function, higher IgE, and a gain in receptor function. However, an effect on exacerbations and tissue inflammation has not been shown. HYPOTHESIS: Allelic substitutions in IL4Ralpha are associated with asthma exacerbations, lower lung function, and tissue inflammation, in particular to mast cells and IgE. METHODS: Two well-characterized cohorts of subjects with severe asthma were analyzed for five single nucleotide polymorphisms (SNPs) in IL4Ralpha. These polymorphisms were compared with the history of severe asthma exacerbations and lung function. In the primary (National Jewish) cohort, these polymorphisms were also compared with endobronchial tissue inflammatory cells and local IgE. RESULTS: In both cohorts, the presence of the minor alleles at E375A and Q551R, which were more common in African Americans, was associated with a history of severe exacerbations and lower lung function. In the National Jewish cohort, the C allele at E375A was associated with higher tissue mast cells and higher levels of IgE bound to mast cells. The significance for most of these associations remained when whites (the larger racial subgroup) were analyzed separately. CONCLUSIONS: SNPs in IL4Ralpha, which are more common in African Americans, are associated with severe asthma exacerbations, lower lung function, and increased mast cell-related tissue inflammation. Further studies of the impact of these mutations in African Americans and on receptor function are indicated.

Adult↗
PubMed2006

Allergen-dependent solubilization of IL-13 receptor alpha2 reveals a novel mechanism to regulate allergy.

BACKGROUND: Allergic sensitization affects half of western populations and often precedes the development of allergic disorders including asthma. Despite the critical role of allergens in the pathogenesis of these disorders, little is known about how allergens modulate the immune response. IL-13 receptor alpha2 (IL-13Ralpha2) is a decoy receptor for IL-13. OBJECTIVE: Although the existence of soluble IL-13Ralpha2 has been documented, the mechanisms underlying its generation are unknown. Many allergens possess protease activity; we investigated whether IL-13Ralpha2 is solubilized in response to allergen treatment. METHODS: We evaluated the ability of allergens to solubilize IL-13Ralpha2 in vitro and in vivo and examined the effect on IL-13 signaling and responses. RESULTS: We determined that treatment of cells with house dust mite (HDM) allergen or purified Dermatophagoides pteronyssinus or Dermatophagoides farinae, but not other allergens, resulted in release of soluble IL-13Ralpha2 that was biologically active and inhibited IL-13 signaling. Prolonged exposure to HDM or treatment with mold allergens resulted in IL-13Ralpha2 degradation. This was associated with increased IL-13 signaling. A single treatment of HDM in vivo resulted in release of IL-13Ralpha2 into the bronchoalveolar lavage (BAL) fluid. BAL fluid from humans also contained IL-13Ralpha2; BAL fluid from individuals with asthma contained less IL-13Ralpha2 than that from controls. CONCLUSION: Allergen exposure can directly affect the level of soluble IL-13Ralpha2 in a way that affects IL-13 signaling and responses. CLINICAL IMPLICATIONS: Soluble IL-13Ralpha2 may be an important biomarker of environmental allergen exposure and asthma.

Allergens↗
PubMed2006

Asthma: defining of the persistent adult phenotypes.

The common disease asthma is probably not a single disease, but rather a complex of multiple, separate syndromes that overlap. Although clinicians have recognised these different phenotypes for many years, they have remained poorly characterised, with little known about the underlying pathobiology contributing to them. Development of targeted therapies for asthma, and phenotype-specific clinical trials have raised interest in these phenotypes. Improved understanding of these phenotypes in complex diseases such as asthma will also improve our ability to link specific genotypes to their associated disease, which should help development of biomarkers. However, there is no standardised method to define asthma phenotypes. This Review analyses some of the methods that have been used to define asthma phenotypes and proposes an integrated method of classification to improve our understanding of these phenotypes.

Adrenal Cortex Hormones↗
PubMed2006

Recent asthma exacerbations: a key predictor of future exacerbations.

OBJECTIVE: The objective of this analysis was to investigate whether patients with severe or difficult-to-treat asthma who experienced recent severe asthma exacerbations are at increased risk of future asthma exacerbations. METHODS: We conducted a 1.5-year prospective analysis of 2780 patients 12 > or =years of age from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens study. Severe exacerbations were defined as either an asthma-related emergency department visit or night of hospitalization in the 3 months prior to study visit; a secondary analysis assessed prior steroid bursts as an independent predictor and outcome. Potential confounding was assessed by statistical adjustment for demographic and clinical factors, as well as asthma severity and asthma control. RESULTS: Compared with patients without a recent severe exacerbation, patients with a recent exacerbation were at increased risk of future exacerbation (odds ratio=6.33; 95% CI 4.57, 8.76), even after adjustment for demographics and clinical factors (odds ratio=3.77; 95% CI 2.62, 5.43), asthma severity (physician-assessed: odds ratio=5.62; 95% CI 4.03, 7.83), National Asthma Education and Prevention Program (odds ratio=5.07; 95% CI 3.62, 7.11), Global Initiative for Asthma (odds ratio=5.32; 95% CI 3.80, 7.47), and asthma control (odds ratio=3.90; 95% CI 2.77, 5.50). CONCLUSION: This analysis suggests that recent severe asthma exacerbations are a strong independent factor predicting future exacerbations and, as such, should be considered as part of the clinical assessment of patients with severe or difficult-to-treat asthma.

Adolescent↗
PubMed2006

Selective downregulation of prostaglandin E2-related pathways by the Th2 cytokine IL-13.

BACKGROUND: Levels of COX-2 and downstream products, such as prostaglandin (PG) E2, are increased in inflammatory settings after stimulation by IL-1beta, LPS, and other innate factors. Although the TH2 cytokines IL-4 and IL-13 have been reported to decrease COX-2 levels in some cell types, neither the effect of these cytokines on other PGE2-related pathways nor their effect in primary human airway epithelial cells has been evaluated. OBJECTIVE: To determine the impact of IL-13 on PGE2 pathways in primary human airway epithelial cells. METHODS: Because PGE2 has anti-inflammatory, antifibrotic, and bronchodilating properties of relevance to asthma, the effect of IL-13 (10 ng/mL for 10 days) on PGE2 pathway elements in first-passage air-liquid interface epithelial cells from 8 endobronchial brushings (5 asthmatic subjects and 3 healthy subjects) was evaluated. mRNA and protein levels for COX-1 and COX-2, membrane-bound PGE synthase 1, 15-PG dehydrogenase, and the receptors EP2 and EP4 were quantified by means of real-time PCR and Western blotting. PGE2 levels in the supernatants were measured by means of enzyme immunoassay. RESULTS: IL-13 significantly inhibited the PGE2 synthetic pathways COX-2 and PGE synthase 1 while upregulating the PGE2 metabolizing enzyme 15-PG dehydrogenase. These enzymatic changes associated and correlated with decreased supernatant PGE2 levels. Significant reductions in the mRNA for EP2 (but not EP4) were also observed. Changes in the PG pathway were both time and dose dependent (n = 3). CONCLUSION: These data suggest that IL-13 induces systematic modulation of proteins related to the production, catabolism, and function of PGE2, which might alter inflammatory and immune responses at the level of the epithelium and the submucosa below. CLINICAL IMPLICATIONS: Modulation of PGE2 pathways by IL-13 might alter inflammatory and repair processes in asthma.

Adult↗
PubMed2006

Subtle immunodeficiency in severe asthma: IgA and IgG2 correlate with lung function and symptoms.

BACKGROUND: Atopy, increased serum IgE and eosinophilic airway inflammation are common in asthma and may indicate aberrant immune responses, but the cause(s) are unknown. It was hypothesized that differences in serum immunoglobulins, immunoglobulin free light chains (FLC) and secretory IgA (sIgA) would exist between subjects with asthma of varying severity and normal subjects, and the levels would correlate with lung function, symptoms and airway inflammation. METHODS: Serum IgG, IgA, IgE and IgM, IgG subclasses and FLC, and bronchoalveolar lavage sIgA were evaluated from 15 normal subjects, 9 mild and 22 severe asthmatics with similar atopic status. Asthma symptoms were obtained by questionnaire, and airway inflammation was assessed by immunostaining for five inflammatory cell types. RESULTS: Immunoglobulin levels in all groups were generally within the normal range. However, IgA and IgG were lower in severe asthmatics than normal subjects (overall p = 0.006 and 0.02, respectively). IgA, but not IgG, correlated with lung function and asthma symptoms (r-values >0.58; p-values <0.009). Although similar among the groups, higher sIgA and IgG(2) also positively correlated with lung function and negatively with asthma symptoms (r-values >0.63; p-values <0.009). IgA and IgG/IgG(1) positively correlated with tissue mast cells. CONCLUSIONS: Subtle alterations in IgA- and IgG(2)-mediated responses in asthma may be disease-related. As their levels are generally normal, it is possible that the quality/repertoire of immune protection provided by these isotypes, perhaps against carbohydrate epitopes, may be altered in asthma.

Adult↗
PubMed2006

Regional fibroblast heterogeneity in the lung: implications for remodeling.

RATIONALE: Excessive deposition of extracellular matrix occurs in proximal airways of individuals with asthma, but fibrosis in distal lung has not been observed. Whether differing fibrotic capacities of fibroblasts from these two regions contribute to this variability is unknown. OBJECTIVES: We compared morphologic and functional characteristics of fibroblasts isolated from proximal airways and distal lung parenchyma to determine phenotypic differences. METHODS: Concurrent proximal airway and distal lung biopsies were obtained by bronchoscopy from subjects with asthma to isolate airway and distal lung fibroblasts, respectively. The following characteristics were compared: morphology, proliferation, alpha-smooth muscle actin expression, and synthesis of procollagen type I and eotaxin-1. RESULTS: Airway fibroblasts (AFs) are morphologically distinct from distal lung fibroblasts (DLFs): they are larger (2.3-fold greater surface area vs. matched DLFs; p = 0.02), stellate in appearance, and with more cytoplasmic projections compared with the spindle-shaped DLFs. AFs synthesized more procollagen type I than did DLFs at baseline (twofold higher; p = 0.003) and after transforming growth factor-beta stimulation (1.4-fold higher; p = 0.02). Similarly, AFs produced more eotaxin-1 than did DLFs at baseline (2.5-fold higher; p = 0.004) and after interleukin-13 stimulation (13-fold higher; p = 0.0001). In contrast, DLFs proliferate more than AFs with serum stimulation (about sixfold greater; p = 0.03). Unstimulated DLFs also expressed more alpha-smooth muscle actin than did corresponding AFs (p = 0.006). CONCLUSIONS: These studies suggest that at least two phenotypes of fibroblast exist in the lung. These phenotypic differences may partially explain the variable responses to injury and repair between proximal airways and distal lung/parenchyma in asthma and other respiratory diseases.

Actins↗
PubMed2006

Asthma in older adults: observations from the epidemiology and natural history of asthma: outcomes and treatment regimens (TENOR) study.

BACKGROUND: The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) was a 3-year, multicenter, observational study of 4,756 patients 6 years or older with severe or difficult-to-treat asthma by physician evaluation. More than 280 pulmonologist and allergist sites across the United States participated. OBJECTIVE: To compare health care utilization (HCU), medication use, asthma control, and quality of life (QoL) in older (> or =65 years; n = 566) and younger (18-64 years; n = 2,912) adult patients in TENOR. METHODS: Patients had to be under a physician's care for at least 1 year and have high medication use or HCU in the past year. Heavy smokers (> or =30 pack-years) and patients with cystic fibrosis were excluded. RESULTS: Although older patients in TENOR had worse lung function as measured by decreased percent predicted forced expiratory volume in 1 second (FEV1) (P < .001), they had significantly lower HCU compared with younger patients. They also had higher use of inhaled corticosteroids and better QoL than younger patients. Older patients reported fewer problems controlling their asthma (P < .001) but reported worse communication with their physicians (P = .02). CONCLUSIONS: Older patients in TENOR appeared to do better than younger patients, despite having worse lung function. Older patients in TENOR may have received more aggressive care than older asthmatic patients in other studies, based on a higher use of inhaled and oral corticosteroids. Whether differences in treatment or disease influenced other physiologic or inflammatory outcomes that contribute to the disconnect between HCU and FEV1 awaits further study.

Adolescent↗
PubMed2006

Gender differences in IgE-mediated allergic asthma in the epidemiology and natural history of asthma: Outcomes and Treatment Regimens (TENOR) study.

BACKGROUND: The TENOR study consists of a large cohort of subjects with severe or difficult-to-treat asthma. The objective of this analysis was to evaluate demographic and clinical characteristics of subjects 12 years of age or older with immunoglobulin E (IgE)-mediated allergic asthma (skin test positive with an IgE level = 30 to =700 IU/mL), and specifically, to assess gender differences in this cohort. METHODS: A total of 4,756 subjects were enrolled by 283 US study sites between January and October 2001. Of those subjects 12 years or older at baseline with an IgE measure and who were skin tested (n = 2,843), 1,783 (63%) were skin test positive and had an IgE level between = 30 to = 700 IU/mL. RESULTS: Compared to males, females reported significantly greater healthcare utilization (steroid bursts in previous 3 months: 50% vs 42%, p < 0.001; unscheduled office visits in previous 3 months: 50% vs 36%, p < 0.0001; missed 1+ days of work/school in previous 2 weeks: 14% vs 10%, p < 0.01). Females also reported significantly more asthma control problems and lower asthma-related quality of life (4.6 +/- 1.3 vs 5.2 +/- 1.2; p < 0.0001); the difference was clinically meaningful. Asthma triggers and allergic comorbidities, such as allergic rhinitis and atopic dermatitis, were more common in female subjects. Despite their overall worse health outcomes, female subjects demonstrated better lung function, had similar treatment patterns, and showed no differences in physician-assessed asthma severity when compared with males. CONCLUSIONS: The reasons for these gender differences in subjects with IgE-mediated allergic asthma are complex, but results from this analysis suggest that detailed evaluations of asthma patients, including symptom-related questions and asthma-related healthcare utilization, are needed to accurately assess asthma severity and control.

Adolescent↗
PubMed2005

Exhaled nitric oxide identifies the persistent eosinophilic phenotype in severe refractory asthma.

BACKGROUND: The fractional concentration of exhaled nitric oxide (FENO) is increased in asthma, correlates with eosinophilic inflammation, and decreases after steroid therapy. OBJECTIVE: We sought to examine whether persistent eosinophilia would be accompanied by an increased FENO level despite steroid therapy in patients with severe refractory asthma (SRA) as manifestations of steroid resistance. METHODS: Subjects with SRA, subjects with mild-moderate asthma, and healthy control subjects had FENO measured, followed by endobronchial biopsy and bronchoalveolar lavage. Tissue and bronchoalveolar lavage inflammatory cells were assessed for all subjects, and eosinophil status (EOS+/EOS-) was determined for subjects with SRA. RESULTS: Twenty-four subjects with SRA, 15 subjects with moderate-mild asthma, and 17 healthy control subjects were studied. Subjects with EOS+ SRA had significantly higher median FENO levels compared with levels in subjects with EOS- SRA (P = .0084) and all other groups. In subjects with SRA, FENO levels correlated with tissue eosinophils (r(s) = 0.54, P = .007), lymphocytes (r(s) = 0.40, P = .003), and mast cells (r(s) = 0.44, P = .05). FENO levels of greater than 72.9 ppb were associated with a sensitivity of 0.56 and a specificity of 1.0 for EOS+ status in subjects with SRA. CONCLUSION: FENO measurement identified the subgroup of subjects with SRA with persistent eosinophilia despite steroid therapy. Further studies are needed on the use of FENO to monitor response to therapy over time in subjects with SRA.

Adult↗
PubMed2005

Severity assessment in asthma: An evolving concept.

BACKGROUND: Guidelines for the clinical management of asthma base specific treatment recommendations on the assessment of disease severity. Thus, the accuracy of such assessments is essential for proper clinical management. The consistency of asthma severity assessment in patients with difficult-to-treat disease is unknown. OBJECTIVE: The objectives of this analysis were to compare the asthma severity assessment according to 3 methodologies in patients from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens study. METHODS: Asthma severity on the basis of the National Asthma Education and Prevention Program and the Global Initiative for Asthma guidelines was compared with physician assessment and benchmarked against asthma-related health care use. Guideline-based asthma severity symptom components were derived from patient-reported questionnaires. Lung function levels were determined by prebronchodilator FEV(1) measurements; asthma-related medication and recent health care use were reported by patients. RESULTS: There was a clear lack of agreement among the asthma severity assessment modalities. Asthma severity was associated with asthma-related health care use, and patients considered to have severe asthma according to both sets of guidelines and physicians' assessment had the highest health care and medication use. CONCLUSION: Classification of asthma severity on the basis of current asthma symptoms and lung function may be useful but not completely reflective of a patient's true asthma condition. Clinical assessment of asthma severity should consider a patient's medication use and consumption of health care resources for asthma exacerbations. Additional studies that apply criteria for asthma severity longitudinally are needed to support recommendations for optimal assessment of asthma severity.

Adolescent↗
PubMed2005

Defective apoptotic cell phagocytosis attenuates prostaglandin E2 and 15-hydroxyeicosatetraenoic acid in severe asthma alveolar macrophages.

RATIONALE: Clearance of apoptotic cells is crucial to the resolution of inflammation and development of fibrosis, but the process is not well understood in normal or diseased human lungs. OBJECTIVES: To determine phagocytosis of apoptotic cells by primary human alveolar macrophages and whether defects in uptake of apoptotic cells are associated with decreases in antiinflammatory/antifibrotic mediators. METHODS: Human bronchoalveolar lavage macrophages (AMphis) from normal control subjects and subjects with mild-moderate or severe asthma were examined in vitro for phagocytosis of apoptotic human T-cell line Jurkats and secretion of inflammatory mediators. MEASUREMENTS AND MAIN RESULTS: AMphis from normal subjects and patients with mild-moderate asthma were able to phagocytose apoptotic cells in response to LPS, resulting in an induction of the antifibrotic and/or antiinflammatory eicosanoids, prostaglandin E2 (PGE2) and 15-hydroxyeicosatetraenoic acid (HETE). In contrast, AMphis from patients with severe asthma had defective LPS-stimulated uptake of apoptotic cells, with associated failure to induce PGE2 and 15-HETE. In addition, LPS-stimulated basal levels of tumor necrosis factor alpha and granulocyte-macrophage colony-stimulating factor were reduced in all patients with asthma, whereas PGE2 and 15-HETE were reduced only in patients with severe asthma. Dexamethasone enhanced specific uptake of apoptotic cells in all subjects, while suppressing inflammatory mediator secretion. CONCLUSIONS: A decrease in AMphis LPS-responsiveness in severe asthma is manifested by defective apoptotic cell uptake and reduces secretion of inflammatory mediators. This may contribute to the chronicity of inflammation and remodeling in lungs of patients with asthma.

Adult↗