Pentraxin 3 deletion aggravates allergic inflammation through a TH17-dominant phenotype and enhanced CD4 T-cell survival.

BACKGROUND: Pentraxin 3 (PTX3) is a multifunctional molecule that plays a nonredundant role at the crossroads between pathogen clearance, innate immune system, matrix deposition, female fertility, and vascular biology. It is produced at sites of infection and inflammation by both structural and inflammatory cells. However, its role in allergen-induced inflammation remains to be tested. OBJECTIVE: We sought to determine the effect of Ptx3 deletion on ovalbumin (OVA)-induced allergic inflammation in a murine model of asthma. METHODS: Bronchoalveolar lavage fluid was collected from patients with severe asthma and healthy subjects, and the level of PTX3 was determined by using ELISA. Ptx3+/+ and Ptx3-/- mice were sensitized and challenged with OVA and bronchoalveolar lavage fluid, and the lungs were collected for assessing inflammation. Lung tissue inflammation and mucus production were assessed by means of flow cytometry and hematoxylin and eosin and periodic acid-Schiff staining, respectively. flexiVent was used to determine airway resistance to methacholine in these mice. RESULTS: Here we report that mice with severe asthma and OVA-sensitized/challenged mice had increased PTX3 levels in the lungs compared with healthy control mice. Mice lacking PTX3 have exaggerated neutrophilic/eosinophilic lung inflammation, mucus production, and airway hyperresponsiveness in an experimental model of OVA-induced asthma. Furthermore, OVA-exposed lung Ptx3-/- CD4 T cells exhibit an increased production of IL-17A, an effect that is accompanied by an increased signal transducer and activator of transcription 3 phosphorylation, reduced IL-2 production, and enhanced activation and survival. Also, we observed an increase in numbers of IL-6- and IL-23-producing dendritic cells in OVA-exposed Ptx3-/- mice compared with those in wild-type control mice. CONCLUSION: Altogether, PTX3 deficiency results in augmented airway hyperresponsiveness, mucus production, and IL-17A-dominant pulmonary inflammation, suggesting a regulatory role of PTX3 in the development of allergic inflammation.

Bronchial thermoplasty failure in severe persistent asthma: a case report.

INTRODUCTION: Bronchial thermoplasty (BT) is an emerging therapy for patients with severe persistent asthma who remain poorly controlled despite standard maximal medical therapy. Thermoplasty elicits asthma control over time by applying thermal radiofrequency energy to airways to ablate underlying smooth muscle. While this therapy is suggested to eliminate such smooth muscle permanently, no human studies have examined the possibility of treatment failure. CASE REPORT: We present a 62-year-old female with severe, refractory asthma symptoms who underwent BT without apparent complications. However, severe symptoms including multiple clinical exacerbations persisted despite BT treatment. Repeat endobronchial biopsy done six months after BT treatment demonstrated persistent smooth muscle hyperplasia in multiple airways that previously had been treated. The patient continued to have uncontrolled, refractory asthma despite multiple therapies. CONCLUSION: This case is the first to describe a failure of BT to reduce or eliminate airway smooth muscle in a patient with severe persistent asthma. It suggests the potential for treatment failure in the management of these patients after BT and highlights the need for further study of potential BT-refractory patients.

Safety and feasibility of bronchial thermoplasty in asthma patients with very severe fixed airflow obstruction: a case series.

OBJECTIVE: Bronchial thermoplasty (BT) can provide relief for patients with severe, uncontrolled asthma despite maximal medical therapy. However, it is unclear whether BT is safe in patients with very severe airflow obstruction. METHODS: We performed BT in eight patients with severe asthma as defined by Expert Panel Report 3 (EPR-3) guidelines who were poorly controlled despite step 5 therapy. Data were available on each subject for 1 year prior to and 15-72 weeks following BT. RESULTS: The mean (±SEM) pre-bronchodilator forced expiratory volume in one second (FEV(1)) prior to BT was 51.8 ± 8.6% of predicted, and the mean (±SEM) number of hospitalizations for asthma in the year prior to BT was 2.9 ± 1.2. No subject had an unexpected severe adverse event due to BT. Among the eight patients with follow-up of at least 15 weeks, there was no significant decline in FEV(1) (p = .4). CONCLUSION: We suggest that BT may be safe for asthma patients with severe airflow obstruction and higher hospitalization rates than previously reported.

Prevalence, clinical features, and CPAP adherence in REM-related sleep-disordered breathing: a cross-sectional analysis of a large clinical population.

PURPOSE: Due to inconsistent definitions used in the literature, the prevalence of rapid eye movement (REM)-related sleep-disordered breathing (SDB) has been quite variable and its clinical significance remains unclear. This study aimed to compare the prevalence of and clinical characteristics between various criteria for defining REM-related SDB. We also investigated how frequently CPAP therapy was recommended in patients with REM-related SDB and if they had lower CPAP adherence compared to non-stage-specific SDB. METHODS: In this cross-sectional study, we evaluated 1,019 consecutive adults referred for a polysomnogram for suspicion of SDB. The prevalence of REM-related SDB was calculated based on "traditional criteria" commonly reported in the literature and a "strict criteria" that minimized the contribution of SDB during non-REM sleep. RESULTS: The prevalence of REM-related SDB ranged from 13.5% to 36.7%. There were no clinically significant differences between the strict definition and the traditional definition of REM-related SDB. REM-related SDB was more prevalent in women, younger individuals and African Americans. Compared to non-stage-specific obstructive sleep apnea (OSA), patients with REM-related SDB were equally symptomatic and hypersomnolent. CPAP titration was recommended in 88% of patients with REM-related SDB vs. 94% of patients with non-stage-specific OSA (p < 0.001). There was no significant difference in CPAP adherence between the two groups. CONCLUSIONS: Regardless of how REM-related SDB is defined, it was highly prevalent in our large clinical cohort. Compared to non-stage-specific OSA, these patients were equally hypersomnolent and adherent to CPAP therapy despite having overall significantly milder OSA. Further research is needed to better establish whether these patients will derive any benefit from long-term CPAP therapy.

Airway Inflammation after Bronchial Thermoplasty for Severe Asthma.

RATIONALE: Bronchial thermoplasty is an alternative treatment for patients with severe, uncontrolled asthma in which the airway smooth muscle is eliminated using radioablation. Although this emerging therapy shows promising outcomes, little is known about its effects on airway inflammation. OBJECTIVES: We examined the presence of bronchoalveolar lavage cytokines and expression of smooth muscle actin in patients with severe asthma before and in the weeks after bronchial thermoplasty. METHODS: Endobronchial biopsies and bronchoalveolar lavage samples from 11 patients with severe asthma were collected from the right lower lobe before and 3 and 6 weeks after initial bronchial thermoplasty. Samples were analyzed for cell proportions and cytokine concentrations in bronchoalveolar lavage and for the presence of α-SMA in endobronchial biopsies. MEASUREMENTS AND MAIN RESULTS: α-SMA expression was decreased in endobronchial biopsies of 7 of 11 subjects by Week 6. In bronchoalveolar lavage fluid, both transforming growth factor-ß1 and regulated upon activation, normal T-cell expressed and secreted (RANTES)/CCL5 were substantially decreased 3 and 6 weeks post bronchial thermoplasty in all patients. The cytokine tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL), which induces apoptosis in several cell types, was increased in concentration both 3 and 6 weeks post bronchial thermoplasty. CONCLUSIONS: Clinical improvement and reduction in α-SMA after bronchial thermoplasty in severe, uncontrolled asthma is associated with substantial changes in key mediators of inflammation. These data confirm the substantial elimination of airway smooth muscle post thermoplasty in the human asthmatic airway and represent the first characterization of significant changes in airway inflammation in the first weeks after thermoplasty.

Gender dimorphism in differential peripheral blood leukocyte counts in mice using cardiac, tail, foot, and saphenous vein puncture methods.

BACKGROUND: In many animal models that investigate the pathology of various diseases, there is a need to monitor leukocyte counts and differentials. However, various researchers use a range of different techniques in male and female laboratory animals to collect such blood variable information. These studies are then compared to one another without consideration of the possibility that different bleeding sites or techniques as well as gender may produce varying results. In light of this, the peripheral blood leukocyte counts and differentials of C57BL/6 male and female mice were determined using four blood-sampling techniques: cardiac, tail, foot, and saphenous vein punctures. METHODS: Blood smears were prepared and stained with Wright-stain for differential cell analysis. The total number of peripheral blood leukocytes was determined with the aid of a hemocytometer. Applying ANOVA and Student t-test analysis made comparisons between groups. RESULTS: The total leukocyte counts obtained using the cardiac puncture method were significantly lower as compared to the other three blood sources; saphenous, tail and foot. There were no significant differences between leukocyte counts of blood samples collected from the tail, saphenous, and foot. Additionally, no significant differences were observed in total leukocyte counts between male and female mice. Differential analysis showed lymphocytes as the predominant cell type present in the peripheral blood of both male and female mice, comprising 75-90% of the total leukocytes. While no significant differences were observed between male and female differential counts of blood collected from saphenous and tail veins, a significant difference in differential counts of blood obtained via cardiac puncture was observed between the male and female groups, suggesting the role of sex hormones. Further, of the four methods, cardiac puncture appeared to be the fastest and more reliable technique, yielding the maximum blood volume with the least amount of stress being exerted on the sampling site. CONCLUSIONS: This information suggests that in studies concerning leukocyte counts and differentials, the animal gender and the sampling site of blood collection should be kept consistent as to avoid introducing any misleading experimental variation, and that cardiac puncture is the best method of blood collection in mice.

Airway smooth muscle in the pathophysiology and treatment of asthma.

Airway smooth muscle (ASM) plays an integral part in the pathophysiology of asthma. It is responsible for acute bronchoconstriction, which is potentiated by constrictor hyperresponsiveness, impaired relaxation and length adaptation. ASM also contributes to airway remodeling and inflammation in asthma. In light of this, ASM is an important target in the treatment of asthma.

Isolation of persistent air leaks and placement of intrabronchial valves.

OBJECTIVES: Alveolar-pleural fistulas causing persistent air leaks are conditions associated with prolonged hospital courses, high morbidity, and possibly increased mortality. Intrabronchial valves serve as a noninvasive therapeutic option for the closure of alveolar-pleural fistulas. METHODS: The present review describes a brief history of, and indications for, the placement of intrabronchial valves in patients with persistent air leaks. The essential steps necessary for placement are air leak isolation, airway sizing, and valve deployment. Additionally, the indications and methods for intrabronchial valve removal, along with the potential complications from intrabronchial valve placement, are described. CONCLUSIONS: The increased use of intrabronchial valves in the treatment of persistent air leaks requires bronchoscopists and clinicians to understand the procedural steps and techniques necessary for intrabronchial valve placement.