Citations

It is now established that airway smooth muscle (ASM) has roles in determining airway structure and function, well beyond that as the major contractile element. Indeed, changes in ASM function are central to the manifestation of allergic, inflammatory, and fibrotic airway diseases in both children and adults, as well as to airway responses to local and environmental exposures. Emerging evidence points to novel signaling mechanisms within ASM cells of different species that serve to control diverse features, including 1) [Ca2+]icontractility and relaxation, 2) cell proliferation and apoptosis, 3) production and modulation of extracellular components, and 4) release of pro- vs. anti-inflammatory mediators and factors that regulate immunity as well as the function of other airway cell types, such as epithelium, fibroblasts, and nerves. These diverse effects of ASM “activity” result in modulation of bronchoconstriction vs. bronchodilation relevant to airway hyperresponsiveness, airway thickening, and fibrosis that influence compliance. This perspective highlights recent discoveries that reveal the central role of ASM in this regard and helps set the stage for future research toward understanding the pathways regulating ASM and, in turn, the influence of ASM on airway structure and function. Such exploration is key to development of novel therapeutic strategies that influence the pathophysiology of diseases such as asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis.

Obesity, metabolic syndrome, and asthma are all rapidly increasing globally. Substantial emerging evidence suggests that these three conditions are epidemiologically and mechanistically linked. Since the link between obesity and asthma appears to extend beyond mechanical pulmonary disadvantage, molecular understanding is necessary. Insulin resistance is a strong, independent risk factor for asthma development, but it is unknown whether a direct effect of insulin on the lung is involved. This review summarizes current knowledge regarding the effect of insulin on cellular components of the lung and highlights the molecular consequences of insulin-related metabolic signaling cascades that could adversely affect lung structure and function. Examples include airway smooth muscle proliferation and contractility and regulatory signaling networks that are associated with asthma. These aspects of insulin signaling provide mechanistic insight into the clinical evidence for the links between obesity, metabolic syndrome, and airway diseases, setting the stage for novel therapeutic avenues targeting these conditions.

SummaryPre‐existing central nervous system (CNS) involvement may influence referral for autologous haematopoietic cell transplantation (AHCT) for patients with non‐Hodgkin lymphoma (NHL). The outcomes of 151 adult patients with NHL with prior secondary CNS involvement (CNS+) receiving an AHCT were compared to 4688 patients without prior CNS lymphoma (CNS−). There were significant baseline differences between the cohorts. CNS+ patients were more likely to be younger, have lower performance scores, higher age‐adjusted international prognostic index scores, more advanced disease stage at diagnosis, more aggressive histology, more sites of extranodal disease, and a shorter interval between diagnosis and AHCT. However, no statistically significant differences were identified between the two groups by analysis of progression‐free survival (PFS) and overall survival (OS) at 5 years. A matched pair comparison of the CNS+ group with a subset of CNS− patients matched on propensity score also showed no differences in outcomes. Patients with active CNS lymphoma at the time of AHCT (n = 55) had a higher relapse rate and diminished PFS and OS compared with patients whose CNS lymphoma was in remission (n = 96) at the time of AHCT. CNS+ patients can achieve excellent long‐term outcomes with AHCT. Active CNS lymphoma at transplant confers a worse prognosis.

IntroductionUnderstanding the course and determinants of sleep disturbances in alcoholic patients may help identify patients at high risk of persistent sleep problems, relapse and guide treatment interventions.MethodsWe prospectively administered the Pittsburgh Sleep Quality Index (PSQI) to all patients (N = 196) admitted to a 1‐month residential treatment program. Our analysis excluded patients with active drug abuse/dependence. Demographic data, psychiatric diagnoses, Patient Health Questionnaire‐9 (PHQ‐9), Alcohol Use Disorders Identification Test (AUDIT) and Inventory of Drug Taking Situations (IDTS) scores were obtained. Univariate and logistic regression analyses were performed using sex, age, hazardous alcohol use, PHQ‐9 scores, hypnotic use, and use of alcohol as a hypnotic as correlates to admission PSQI scores and improvement in PSQI scores.ResultsA total of 119 alcoholic patients met inclusion criteria (mean age 50.6 ± 13.2 years). The rates of sleep disturbances at admission and discharge were 69.3% and 49.1%, respectively. Self report of using alcohol to fall asleep and use of hypnotics were associated with elevated PSQI scores. Total PSQI scores improved over 4 weeks (p < .001). Change in PSQI scores was not effected by gender, use of hypnotics, hazardous alcohol use, use of alcohol as a hypnotic or co‐morbid psychiatric diagnosis. Older age predicted improvement in PSQI scores in patients with sleep disturbances (p = .004).ConclusionWhile a large proportion of alcoholics had sleep disturbances upon admission and at discharge from a residential treatment program, only older age was associated with improvements in sleep disturbances during early alcohol recovery. (Am J Addict 2014;23:21–26)

Abstract Inflammation elevates intracellular Ca2+ ([Ca2+]i) concentrations in airway smooth muscle (ASM). Store-operated Ca2+ entry (SOCE) is an important source of [Ca2+]i mediated by stromal interaction molecule–1 (STIM1), a sarcoplasmic reticulum (SR) protein. In transducing SR Ca2+ depletion, STIM1 aggregates to form puncta, thereby activating SOCE via interactions with a Ca2+ release-activated Ca2+ channel protein (Orai1) in the plasma membrane. We hypothesized that STIM1 aggregation is enhanced by inflammatory cytokines, thereby augmenting SOCE in human ASM cells. We used real-time fluorescence microscopic imaging to assess the dynamics of STIM1 aggregation and SOCE after exposure to TNF-α or IL-13 in ASM cells overexpressing yellow fluorescent protein–tagged wild-type STIM1 (WT-STIM1) and STIM1 mutants lacking the Ca2+-sensing EF-hand (STIM1-D76A), or lacking the cytoplasmic membrane binding site (STIM1ΔK). STIM1 aggregation was analyzed by monitoring puncta size during the SR Ca2+ depletion induced by cyclopiazonic acid (CPA). We found that puncta size was increased in cells expressing WT-STIM1 after CPA. However, STIM1-D76A constitutively formed puncta, whereas STIM1ΔK failed to form puncta. Furthermore, cytokines increased basal WT-STIM1 puncta size, and the SOCE triggered by SR Ca2+ depletion was increased in cells expressing WT-STIM1 or STIM1-D76A. Meanwhile, SOCE in cells expressing STIM1ΔK and STIM1 short, interfering RNA (siRNA) was decreased. Similarly, in cells overexpressing STIM1, the siRNA knockdown of Orai1 blunted SOCE. However, exposure to cytokines increased SOCE in all cells, increased basal [Ca2+]i, and decreased SR Ca2+ content. These data suggest that cytokines induce a constitutive increase in STIM1 aggregation that contributes to enhanced SOCE in human ASM after inflammation. Such effects of inflammation on STIM1 aggregations may contribute to airway hyperresponsiveness.

Abstract This study was designed to characterize the clinical spectrum and course of tracheobronchial involvement in Wegener's granulomatosis (WG). Of the 51 patients with biopsy-proven WG who underwent bronchoscopy at least once at our institution between January 1982 and November 1993, 30 (59%) had endobronchial abnormalities due to WG. Initial findings included subglottic stenosis in five (17%), ulcerating tracheobronchitis with or without inflammatory pseudotumors in 18 (60%), tracheal or bronchial stenosis without inflammation in four (13%), and hemorrhage without identifiable source in two (4%) patients. Nine patients with ulcerating tracheobronchitis on initial study had subsequent bronchoscopies for continued symptoms, which in seven cases documented the progression from ulcerating tracheobronchitis to stenosis without inflammation. Bronchoscopic interventions included dilation by rigid bronchoscope in three, YAG-laser treatment in one, and placement of silastic airway stents in three patients. Only the stents provided persistent airway patency. Endobronchial biopsies were performed on 21 occasions in 17 patients. Half of the specimens were helpful in establishing the diagnosis and in all but three in assessing disease activity. While antineutrophil cytoplasmic antibody titers reflect overall disease activity, no correlation with endobronchial inflammatory activity was apparent.