Nonasthmatic Individuals Research Articles

Beyond the Immune System: The Role of Resident Cells in Asthma and COPD

Beyond the Immune System: The Role of Resident Cells in Asthma and COPD

Obesity, expiratory flow limitation and asthma symptoms

Obesity is associated with poor asthma control, but the reason for this is unclear. Reduction in operating lung volume, as occurs in obesity, and bronchoconstriction, as occurs in asthma, can increase expiratory flow limitation during tidal breathing (EFLt), which may in turn increase respiratory symptoms. The aim of this study was to determine the effect of obesity on EFLt at baseline and after bronchoconstriction in non-asthmatic and asthmatic subjects, and to determine the association between EFLt, and respiratory symptoms. Data from previously published studies in non-asthmatic and asthmatic subjects were reanalyzed using an index of EFLt derived from respiratory system reactance measured by the forced oscillation technique. The analysis showed that during bronchoconstriction both non-asthmatic and asthmatic obese individuals were more likely to develop EFLt than non-obese subjects, despite similar changes in FEV1. Furthermore the index of EFLt was a significant determinant of the severity of breathlessness during challenge in non-asthmatic subjects, and of asthma symptom control in asthmatic subjects following anti-inflammatory treatment. These studies suggest that the combination of bronchoconstriction and low resting lung volume increase the risk of EFLt, and that this altered response to bronchoconstriction may increase the severity of symptoms and lead to worse asthma control.

Combined Beta-Agonists and Corticosteroids Do Not Inhibit Extracellular Matrix Protein Production In Vitro

Background. Persistent asthma is characterized by airway remodeling. Whereas we have previously shown that neither β 2-agonists nor corticosteroids inhibit extracellular matrix (ECM) protein release from airway smooth muscle (ASM) cells, the effect of their combination is unknown and this forms the rationale for the present study. Methods. ASM cells from people with and without asthma were stimulated with TGFβ1 (1 ng/ml) with or without budesonide (10−8 M) and formoterol (10−10 and 10−8 M), and fibronectin expression and IL-6 release were measured by ELISA. Bronchial rings from nonasthmatic individuals were incubated with TGFβ1 (1 ng/ml) with or without the drugs, and fibronectin expression was measured using immunohistochemistry. Results. Budesonide stimulated fibronectin deposition, in the presence or absence of TGFβ1, and this was partially reversed by formoterol (10−8 M) in both asthmatic and nonasthmatic cells. Budesonide and formoterol in combination failed to inhibit TGFβ-induced fibronectin in either cell type. A similar pattern of expression of fibronectin was seen in bronchial rings. TGFβ1-induced IL-6 release was inhibited by the combination of drugs. Conclusion. Current combination asthma therapies are unable to prevent or reverse remodeling events regulated by ASM cells.

Serum IgE Reactivity Profiling in an Asthma Affected Cohort

BackgroundEpidemiological evidence indicates that atopic asthma correlates with high serum IgE levels though the contribution of allergen specific IgE to the pathogenesis and the severity of the disease is still unclear.MethodsWe developed a microarray immunoassay containing 103 allergens to study the IgE reactivity profiles of 485 asthmatic and 342 non-asthmatic individuals belonging to families whose members have a documented history of asthma and atopy. We employed k-means clustering, to investigate whether a particular IgE reactivity profile correlated with asthma and other atopic conditions such as rhinitis, conjunctivitis and eczema.ResultsBoth case-control and parent-to-siblings analyses demonstrated that while the presence of specific IgE against individual allergens correlated poorly with pathological conditions, particular reactivity profiles were significantly associated with asthma (p<10E-09). An artificial neural network (ANN)-based algorithm, calibrated with the profile reactivity data, correctly classified as asthmatic or non-asthmatic 78% of the individual examined. Multivariate statistical analysis demonstrated that the familiar relationships of the study population did not affect the observed correlations.ConclusionsThese findings indicate that asthma is a higher-order phenomenon related to patterns of IgE reactivity rather than to single antibody reactions. This notion sheds new light on the pathogenesis of the disease and can be readily employed to distinguish asthmatic and non-asthmatic individuals on the basis of their serum reactivity profile.

Association of ADAM33 gene polymorphisms with adult-onset asthma and its severity in an Indian adult population

ADAM33, a member of the ADAM (a disintegrin and metalloprotease) gene family, is an asthma susceptibility gene originally identified by positional cloning. In the present study, we investigated the possible association of five single-nucleotide polymorphisms (SNPs) in the ADAM33 (rs511898, rs528557, rs44707, rs597980 and rs2787094) with adult-onset asthma in an Indian population. The study included 175 patients with mild intermittent (n = 44), mild persistent (n = 108) or moderate persistent (n = 23) subgroups of asthma, and 253 nonasthmatic control individuals. SNPs were genotyped with the help of restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR) method, and data were analysed using chi-square test and logistic regression model. Bonferroni's correction for multiple comparisons was applied for each hypothesis. Genotypes and allele frequencies of SNPs rs511898 and rs528557 were significantly associated with adult-onset asthma (P = 0.010-<0.001). A significant association of the homozygous mutant genotype and mutant alleles of SNPs rs2787094, rs44707 and rs597980 with the asthma was also observed (P = 0.020-<0.001). A positive association between asthma and haplotypes AGCCT, GGCCT, AGACT, GCAGT, GGACT, ACCCC and AGACC were also found (P = 0.036-<0.001, OR = 2.07-8.49). Haplotypes AGCGT, GCAGC, ACAGC, ACAGT, GGAGC and GGCGT appear to protect against asthma (P = 0.013-<0.0001, OR = 0.34-0.10). Our data suggest that ADAM33 gene polymorphisms serve as genetic risk factors for asthma in Indian adult population.

Asthma And Proinflammatory Conditions: A Population-based Retrospective Matched Cohort Study

Abstract Objective To determine the association between asthma and proinflammatory conditions. Participants and Methods This population-based retrospective matched cohort study enrolled all asthmatic patients among Rochester, Minnesota, residents between January 1, 1964, and December 31, 1983. For each asthmatic patient, 2 age-and sex-matched nonasthmatic individuals were drawn from the same population. The asthmatic and nonasthmatic cohorts were followed forward in the Rochester Epidemiology Project diagnostic index for inflammatory bowel disease (IBD), rheumatoid arthritis (RA), diabetes mellitus (DM), and coronary heart disease (CHD) as outcome events. Data were fitted to Cox proportional hazards models. Results We identified 2392 asthmatic patients and 4784 nonasthmatic controls. Of the asthmatic patients, 1356 (57%) were male, and mean age at asthma onset was 15.1 years. Incidence rates of IBD, RA, DM, and CHD in nonasthmatic controls were 32.8, 175.9, 132.0, and 389.7 per 100,000 person-years, respectively; those for asthmatic patients were 41.4, 227.9, 282.6, and 563.7 per 100,000 person-years, respectively. Asthma was associated with increased risks of DM (hazard ratio, 2.11; 95% confidence interval, 1.43-3.13; P P =.02) but not with increased risks of IBD or RA. Conclusion Although asthma is a helper T cell type 2–predominant condition, it may increase the risks of helper T cell type 1–polarized proinflammatory conditions, such as CHD and DM. Physicians who care for asthmatic patients need to address these unrecognized risks in asthmatic patients.

Detection of immunological biomarkers correlated with asthma control and quality of life measurements in sera from chronic asthmatic patients.

Clinical outcomes of patients with asthma are highly variable. Immunological biomarkers associated with asthma control have not been elucidated. To identify the association between clinical control of asthma and serum immunological profiles of asthmatics and compare these profiles with those of healthy controls by using a multiplex assay. Sera were obtained from 28 nonsmokers 18 to 55 years of age with moderate and severe persistent asthma. Patients were classified as having well-controlled (WC, n = 14) or poorly controlled (PC, n = 14) asthma based on their responses to the Asthma Control Questionnaire and Asthma Quality of Life Questionnaire. Sera from nonasthmatic control individuals (NAC, n = 14) were used for comparison. Levels of 50 analytes, including cytokines, chemokines, angiogenic, and growth factors, were determined, using a multiplex assay. Twelve of the 29 cytokines levels were significantly higher in patients with asthma than in NACs, but only interferon gamma levels were significantly lower in patients with asthma than in the NAC group. Among these, interleukin (IL)-3 and IL-18 levels were significantly higher in the PC group than the WC group. Five of the 12 tested chemokine levels were significantly higher in patients with asthma than in NACs. Five of six growth factor levels were significantly higher in patients with asthma than in NACs, and 3 were higher in PC than WC. Interleukin-18, fibroblast growth factor, hepatocyte growth factor, and stem cell growth factor-beta were positively correlated with poor asthma control and negatively with quality of life scores. Increased serum levels of fibroblast growth factor, hepatocyte growth factor, and stem cell growth factor-beta might be useful biomarkers of asthma control status and targets of future asthma therapy.

Factors Associated with Furry Pet Ownership Among Patients with Asthma

Background. Exposure to indoor allergens is an established risk factor for poor asthma control. Current guidelines recommend removing pets from the home of patients with asthma. Objectives. This cross-sectional study was conducted to determine the prevalence of furry pet ownership in asthmatics compared to nonasthmatics and to identify factors associated with furry pet ownership among those with asthma. Secondary analysis assessed characteristics among asthmatics that might be associated with allowing a furry pet into the bedroom. Methods. Using data from The National Asthma Survey collected from 2003 to 2004, we carried out univariate and multiple regression analyses, in 2009, to identify independent predictors of furry pet ownership in asthma sufferers after controlling for potential confounders. Results. Overall, asthmatics were more likely to own a furry pet than nonasthmatic individuals in the general population (49.9% versus 44.8%, p < .001). Multivariate analysis showed that female sex, older age, white race, and high income were independent predictors of furry pet ownership among asthmatics. Additionally, 68.7% of patients with asthma who own a furry pet allowed them into their bedroom. Higher income and carrying out ≤2 environmental control practices in the home were associated with increased likelihood of allowing a furry pet into the bedroom. Conclusions. Furry pet ownership is equally or more common among asthmatics compared to those without asthma. The majority of asthmatics with furry pets allow them into the bedroom. Recognizing and addressing these problems may help decrease asthma morbidity.

Concentrated ambient fine particles and not ozone induce a systemic interleukin-6 response in humans

Epidemiological studies have established significant associations between ambient pollutants, including fine particulate matter (PM2.5) and ozone (O3), and cardiopulmonary morbidity and mortality. One mechanism that has been proposed is a pulmonary/systemic inflammatory response. Although controlled human exposure studies have examined the independent inflammatory responses of PM2.5 and O3, no studies have previously examined their joint effects. The study objective was to examine the independent and combined associations between ambient PM2.5 and O3 and acute respiratory/inflammatory responses. Using their concentrated ambient particle (CAP) facility for PM2.5, the authors studied 10 mild asthmatic and 13 nonasthmatic individuals. The 2-h exposures included CAP (range 48–199 μg/m3) and filtered air (FA), with/without O3 (120 ppb), in a randomized block design. Response measures included pulmonary function and inflammatory indices in induced sputum (interleukin [IL]-6, cytology) and blood (IL-6, tumor necrosis factor [TNF]-α) measured before and after exposures. Three hours post exposure, there was an increase in blood levels of IL-6, but only after CAP alone exposures; the IL-6 increase was associated with increasing PM2.5 mass concentration (p = .005). Some individuals switched to shallow breathing during CAP+O3, possibly accounting for an attenuation of the resultant blood IL-6 response. Asthmatic and nonasthmatic responses were similar. There were no adverse changes in pulmonary function or other inflammatory measures. The study demonstrated an acute IL-6 response to PM2.5, providing evidence to support the epidemiological findings of associations between ambient levels of particles and cardiopulmonary morbidity and mortality.

MUC7 Polymorphisms Are Associated With a Decreased Risk of a Diagnosis of Asthma in an African American Population

PurposeMucin glycoproteins contribute to lung pathophysiology in asthma. The protein backbone of mucin glycoproteins is encoded by specific MUC genes, which exhibit a high degree of polymorphisms that generate a...

Effect of natural seasonal pollen exposure and repeated nasal allergen provocations on elevation of exhaled nitric oxide

Exhaled nitric oxide (FENO) is a marker for allergic airway inflammation. We wondered whether in patients with intermittent allergic rhinitis only (i) natural pollen exposure and (ii) artificial pollen exposure by repeated nasal allergen provocations may lead to an elevation of FENO. In two prospective studies, we compared the FENO of nonatopic controls with the FENO of nonasthmatic individuals with mild intermittent rhinitis to tree and/or grass pollen. Study I: 13 atopic individuals and seven controls had measurements of FENO, blood eosinophils and eosinophilic cationic protein (ECP) before, during and after pollen season. Study II: 16 atopic individuals and 12 controls had nasal allergen provocations on four following days out of pollen season, with daily measurements of FENO before, 2 and 6 h after provocation, and determination of blood eosinophils, ECP and FEV1 at baseline, on days 5 and 10-12. Natural pollen exposure (study I) caused a significant elevation of FENO in allergic individuals. Nasal allergen provocations (study II) did not elicit a statistically significant rise neither of FENO nor of blood eosinophils between baseline and day 5. However, a subgroup of four individuals with a rise of blood eosinophils during nasal allergen provocations showed also a rise of FENO. We suppose that in allergic rhinitis a concomitant reaction of the bronchial system is dependent on a strong local inflammation leading to a generalized immune stimulation.

Human Airway Smooth Muscle Cells from Asthmatic Individuals Have CXCL8 Hypersecretion Due to Increased NF-κB p65, C/EBPβ, and RNA Polymerase II Binding to the CXCL8 Promoter

CXCL8 is a neutrophil and mast cell chemoattractant that is involved in regulating inflammatory cell influx in asthma. Here, we investigated the transcriptional mechanism involved in CXCL8 induction by TNF-alpha in cultured human airway smooth muscle (HASM) cells and compared these in cells from nonasthmatic and asthmatic individuals. Transfection studies with mutated CXCL8 promoter constructs identified NF-kappaB, activating protein-1, and CAAT/enhancer binding protein (C/EBP)beta as key transcription factors, and binding of these three transcription factors to the CXCL8 promoter after TNF-alpha stimulation was confirmed by chromatin immunoprecipitation analysis. Cells derived from asthmatic individuals produced significantly higher levels of CXCL8 than nonasthmatic cells both basally and following 24 h of stimulation with TNF-alpha (p < 0.001). Furthermore, chromatin immunoprecipitation studies detected increased binding of NF-kappaB p65 and RNA polymerase II to the CXCL8 promoter of asthmatic HASM cells both in the presence and absence of TNF-alpha stimulation. This was not due to either an increased activation or phosphorylation of NF-kappaB per se or to an increase in its translocation to the nucleus. Increased binding of C/EBPbeta to the CXCL8 promoter of unstimulated cells was also detected in the asthmatic HASM cells. Collectively these studies show that HASM cells from asthmatic individuals have increased CXCL8 production due to the presence of a transcription complex on the CXCL8 promoter, which contains NF-kappaB, C/EBPbeta, and RNA polymerase II. This is the first description of an abnormality in transcription factor binding altering chemokine expression in airway structural cells in asthma.

T cells and eosinophils in bronchial smooth muscle cell death in asthma

Bronchial smooth muscle cells (SMC) proliferate, express adhesion molecules, secrete cytokines and thus efficiently contribute to the pathogenesis of asthma. The aim of the study was to investigate whether, and by which mechanism, T cells and eosinophils can cause death of airway SMC. The T cell- and eosinophil-induced cell death was analysed in primary human bronchial SMC cultures as well as in bronchial biopsy specimens from non-asthmatic and asthmatic individuals. Bronchial SMC death showed characteristic morphological features of apoptosis in 3-6 days cultures with inflammatory cytokines (IFN-gamma, TNF-alpha), soluble death ligands [sFasL, TNF-related apoptosis-inducing ligand (TRAIL)] and activated T-helper type 1 (Th1) and Th2 cell supernatants. The recombinant eosinophil cationic protein induced SMC necrosis within 1 h. Resting SMC expressed the death receptors TNFR1, TNFR2, Fas, TRAILR1, TRAILR2 and membrane FasL as a death-inducing ligand. IFN-gamma and TNF-alpha up-regulated TNFR1, TNFR2, Fas and membrane FasL on SMC. TNF-alpha up-regulated TRAILR1 and TRAILR2; sFasL up-regulated TNFR2. The intracellular caspase-3 activation in SMC was significantly increased by IFN-gamma, sFasL, TRAIL, Th1 and Th2 cell supernatants. Increased expression of TRAIL in asthmatics, but not in non-asthmatic individuals was demonstrated in situ. The apoptosis receptors TRAILR1 and TRAILR2 were expressed in SMC and epithelial cells both in healthy and asthmatic biopsies. Prominent apoptosis of SMC was observed in fatal asthma, but not intermittent asthma biopsies. The demonstration of bronchial SMC death both by apoptosis and necrosis indicates the essential role of T cells and eosinophils in the bronchial tissue injury particularly in the severe asthma.

Association of Ambient Ozone Exposure with Airway Inflammation and Allergy in Adults with Asthma

Rationale. Previous studies have demonstrated associations of high ozone levels with increased epidemiologic as well as lung function measures of asthma activity. Objectives. In an observational study during the summer months, we hypothesized that higher ambient ozone levels are associated with more frequent symptoms, higher airway and systemic inflammation, as well as worse lung function in asthmatics as compared with non-asthmatic individuals. Methods. Thirty-eight asthmatics and thirteen healthy control subjects residing in metropolitan Atlanta were enrolled during peak ozone season. Medical histories, quality-of-life questionnaires, spirometry, serum immunoglobulin (IgE), peripheral eosinophil counts, and exhaled nitric oxide (NO) were obtained during study visits. Personal ozone exposures over the 2 days before presentation were estimated based on location and activity surveys. Main results. Upper airway symptoms were more frequent in asthmatics. Higher levels of ozone were associated with worse airflow obstruction, lower quality of life scores, greater eosinophilia, and higher exhaled NO levels in asthmatics. Finally, both asthmatics and non-asthmatics with allergies showed associations between air quality and airway inflammation. Conclusions: In adults with asthma but not controls studied during peak ozone season, increasing ozone exposure predicted lower lung function and increased biomarkers of respiratory and systemic inflammation. These associations were enhanced in atopic participants, both with and without asthma. Importantly, the study findings were noted while atmospheric ozone levels were predominantly within the current and revised national air quality standards.

Effect of Fish Oil-Derived Omega-3 Polyunsaturated Fatty Acid Supplementation on Exercise-Induced Bronchoconstriction and Immune Function in Athletes

Exercise-induced bronchoconstriction (EIB) is a condition in which vigorous physical activity triggers acute airway obstruction in asthmatic and nonasthmatic individuals with hyperresponsive airways. Studies have shown that inflammatory mediators and contraction of airway smooth muscle are central components in the pathogenesis of EIB, and it has long been recognized that leukotrienes and prostaglandins play an important role in the EIB response. Clinical responses to current therapy, such as leukotriene modifiers and corticosteroids are heterogeneous, and even with optimal treatment there is a substantial burden of unaddressed disease. While daily medications such as leukotriene modifiers provide only modest protection against symptoms, prolonged use of several medications can result in reduced effectiveness or tachyphylaxis. Although the treatment of EIB almost exclusively involves pharmacotherapy, there is now convincing evidence that dietary modification has the potential to reduce the severity of this condition. Omega-3 polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in fish oils, compete with arachidonic acid as substrates for the formation of proinflammatory mediators, such as leukotrienes, prostaglandins, and cytokines. Studies have shown that 3 weeks of fish oil supplementation, rich in EPA and DHA, reduces exercise-induced airway narrowing, airway inflammation, and bronchodilator use in elite athletes and asthmatic individuals with EIB. Based on the evidence to date, fish oil supplementation may represent a potentially beneficial treatment intervention for athletes and asthmatic individuals with EIB. From this, it follows that physicians should pay more attention to what their asthma/EIB patients eat, and incorporate dietary assessment and nutritional counseling in their everyday practice.

The Predictive Value of IgE as Biomarker in Asthma

Background. The evidence for a causal relationship between allergens and asthma depends on epidemiologic findings showing a strong association between specific immunoglobulin E (IgE) antibodies or total IgE and asthma. Objective. To clarify the relationship between total serum IgE levels and asthma. Study design. A cross–sectional study. Patients and methods. A total of 562 asthmatic patients were included in the study, and their age range was from 17 to 52 years. The subjects included in the study were outpatients from the Asthma and Allergy Centre or Samara General Hospital outpatients Clinic. The diagnosis of asthma was performed by a specialist physician and was established according to the National Heart Blood and Lung Institute/World Health Organization (NHLBI/WHO) workshop on the Global Strategy for Asthma. Results. This study indicated that mean serum IgE level was 554 ± 447 IU/mL in asthmatic patients, while that of the control population was 69 ± 33 IU/mL. There was no overlap in the values of 95% confidence interval (CI) of higher control limit and lower asthmatic limit values. Addition of two standard deviations to the mean IgE value of the control group (134 IU/mL) does not overlap with the lower 95% CI of the asthmatic group. However, serum IgE was within normal values in 5.9% of asthmatic patients in our study population. There was an inverse correlation between serum IgE levels and forced expiratory volume in 1 second (FEV1) predicted percent for patients with asthma (r = −0.73, p < 0.0001). The predictive value of serum IgE in asthma was determined using Receiver Operating Characteristics (ROC) curve method. From the ROC curve, it can be seen that it is possible to get both high sensitivity and high specificity if the right cut–off value was chosen. In fact, a cut–off of 200 IU/mL would indicate sensitivity of 93% and specificity of 91% in this group of patients and control subjects. Following immunotherapy there was 36% reduction in total serum IgE level. The value of IgE was significantly reduced (p < 0.001) from 956 ± 378 IU/mL at baseline to 613 ± 194 IU/mL after treatment. Conclusion. Serum IgE level was predictive in asthma, and it may be used to differentiate between asthmatic and non-asthmatic individuals in conjunction with other biomarkers. Specific immunotherapy reduced serum total IgE level in 36% of patients with asthma.

Lentiviral-mediated GATA-3 RNAi Decreases Allergic Airway Inflammation and Hyperresponsiveness

GATA-3 is the key transcriptional factor for Th2 commitment in T cells and is strongly associated with asthma and allergic disease. We studied the silencing of the GATA-3 gene expression using RNA interference (RNAi) delivered by a lentiviral vector, to evaluate the therapeutic role of GATA-3 short hairpin RNAs (shRNAs) in a murine model of asthma. Mice were sensitized with OVA and instilled intratracheally (IT) with GATA-3 shRNAs lentiviral vector (Lenti-si-GATA-3) once, 48 hours before challenge. After three challenges with the OVA antigen, the mice were assessed for airway hyperresponsiveness (AHR) and inflammation. With infection of Lenti-si-GATA-3 in EL-4 cells, GATA-3 gene expression was abrogated and downstream Th2 cytokines, such as interleukin-4 (IL-4) and IL-5, were also significantly inhibited. IT delivery of Lenti-si-GATA-3 in OVA-immunized mice resulted in a strong inhibition of local GATA-3 gene expression. Treatment with Lenti-si-GATA-3 successfully alleviated OVA-induced airway eosinophilia and Th2 cytokine release. While evaluating AHR by means of enhanced pause (Penh) and pulmonary resistance (R(L)) using body plethysmography, it was found that the administration of Lenti-si-GATA-3 had significantly decreased AHR in OVA-immunized mice. These results suggest that inhibition of GATA-3 gene expression by shRNAs lentiviral vectors strongly attenuates antigen-induced airway inflammation and hyper-responsiveness in mice.

Mechanisms of induction of airway smooth muscle hyperplasia by transforming growth factor-β

Airway smooth muscle (ASM) hyperplasia is a characteristic feature of the asthmatic airway, but the underlying mechanisms that induce ASM hyperplasia remain unknown. Because transforming growth factor (TGF)-beta is a potent regulator of ASM cell proliferation, we determined its expression and mitogenic signaling pathways in ASM cells. We obtained ASM cells by laser capture microdissection of bronchial biopsies and found that ASM cells from asthmatic patients expressed TGF-beta1 mRNA and protein to a greater extent than nonasthmatic individuals using real-time RT-PCR and immunohistochemistry, respectively. TGF-beta1 stimulated the growth of nonconfluent and confluent ASM cells either in the presence or absence of serum in a time- and concentration-dependent manner. The mitogenic activity of TGF-beta1 on ASM cells was inhibited by selective inhibitors of TGF-beta receptor I kinase (SD-208), phosphatidylinositol 3-kinase (PI3K, LY-294002), ERK (PD-98059), JNK (SP-600125), and NF-kappaB (AS-602868). On the other hand, p38 MAPK inhibitor (SB-203580) augmented TGF-beta1-induced proliferation. To study role of the Smads, we transduced ASM cells with an adenovirus vector-expressing Smad4, Smad7, or dominant-negative Smad3 and found no involvement of these Smads in TGF-beta1-induced proliferation. Dexamethasone caused a dose-dependent inhibition in TGF-beta1-induced proliferation. Our findings suggest that TGF-beta1 may act in an autocrine fashion to induce ASM hyperplasia, mediated by its receptor and several kinases including PI3K, ERK, and JNK, whereas p38 MAPK is a negative regulator. NF-kappaB is also involved in the TGF-beta1 mitogenic signaling, but Smad pathway does not appear important.

Adult asthmatics display exaggerated IFNγ responses to human metapneumovirus and respiratory syncytial virusThis paper is one of a selection of papers in this Special Issue, entitled International Symposium on Recent Advances in Molecular, Clinical, and Social Medicine, and has undergone the Journal's usual peer-review process.

Human metapneumovirus and respiratory syncytial virus are RNA viruses associated with lower respiratory tract infections. Regular symptomatic re-infection and sequelae are common, particularly in individuals with pre-existing respiratory diseases, such as asthma. Our understanding of virus-dependent cytokine responses and potential differences between allergic asthmatics and non-asthmatics is limited. To test our hypothesis that adults with mild allergic asthma, the most common form of this disease, exhibit distinct pro-inflammatory responses, we developed a model using acute in vitro infection of fresh peripheral blood mononuclear cells. For both viruses, the production of innate-immunity-associated IL-6 and IL-10 was indistinguishable in the 2 populations. Type 1 cytokine production dominated adaptive immune responses in both asthmatic and non-asthmatic individuals. Surprisingly, asthmatics exhibited stronger pro-inflammatory IFNgamma production in response to human metapneumovirus than non-asthmatic adults (p = 0.01), with a similar, but statistically nonsignificant trend in the respiratory-syncytial-virus-stimulated response. Neutralizing IL-10 did not enhance the intensity of IFNgamma responses, demonstrating that this pro-inflammatory bias is not counter-regulated by IL-10. Finally, anti-TLR4 blocked lipopolysaccharide, but not respiratory-syncytial-virus-driven cytokine production. Collectively, the data demonstrate that asthma is characterized by markedly stronger pro-inflammatory IFNgamma responses to pneumoviruses than their non-asthmatic counterparts. This distinctive pattern of viral immunity may contribute to a worsening of asthma symptoms during respiratory virus infections.

Allergic Bronchopulmonary Aspergillosis Coupled with Broncholithiasis in a Non-asthmatic Patient

Allergic bronchopulmonary aspergillosis (ABPA), an asthmatic disease, is caused primarily by hypersensitivity to Aspergillus species. ABPA is rarely observed in the absence of asthma, which is, in fact, the principle criterion for its diagnosis. Here, we report the case of a 36-yr-old woman without a history of bronchial asthma, who manifested a localized pneumonic consolidation, coupled with broncholithiasis. Pathologic examinations of bronchoscopic biopsy specimens and resected surgical specimens revealed features typical of ABPA. This is a very rare case of ABPA coupled with broncholithiasis in a non-asthmatic individual.