Programmed cell death-1 pathway inhibition in myeloid malignancies: implications for myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic diseases that belong to the spectrum of myeloid malignancies (MyMs), which also include myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic myelogenous leukemia (CML). While hematopoietic stem cell transplantation (HSCT) is a potentially curative therapeutic approach to many MyMs, the associated morbidity and mortality have necessitated the development of non-HSCT therapeutics for symptom management and disease course modification. Immune checkpoint inhibition, in particular along the programmed cell death protein 1 (PD-1)/B7-H1 (PD-L1) axis, is an established strategy in solid tumors with potential as an adjunctive therapy in hematologic malignancies. Seminal studies suggest that the pro-inflammatory microenvironment of MyMs can suppress T lymphocyte-mediated immunity via PD-1 signaling and that response to mainstay epigenetic therapies for MyMs may be governed by PD-1 gene regulation. Although the role of PD-1 signaling in MPN pathogenesis and progression is as yet unclear, research in MPN patients has revealed expansion of myeloid-derived suppressor cells (MDSCs), which may effect host immune tolerance of tumor via temporally and spatially specific activation of PD-1/PD-L1 signaling. The current understanding of immune dysfunction in MPNs and analogous MyMs offers a compelling rationale to study PD-1/PD-L1 inhibition in patients as a novel treatment option.

Prelimbic BDNF and TrkB signaling regulates consolidation of both appetitive and aversive emotional learning.

The medial prefrontal cortex (mPFC) is known to regulate executive decisions and the expression of emotional memories. More specifically, the prelimbic cortex (PL) of the mPFC is implicated in driving emotional responses via downstream targets including the nucleus accumbens and amygdala, but mechanisms are yet to be fully understood. Therefore, we investigated whether prelimbic cortical brain-derived neurotrophic factor (BDNF) signaling through the high-affinity tyrosine kinase receptor B (TrkB) receptor may serve as a molecular mechanism underlying emotional memory encoding. Here, we utilized viral-mediated inducible bdnf deletion within the PL, as well as TrkB(F616A) mutant mice, wherein TrkB receptor point mutation results in its being highly sensitive to inhibition by small PP1-derivative molecules, serving as a specific TrkB inhibitor. The site-specific TrkB antagonism and viral-mediated bdnf deletion within the PL resulted in deficits in both cocaine-dependent associative learning and fear expression. Deficiencies were rescued by the novel TrkB agonist 7,8-dihydroxyflavone, indicating that PL BDNF expression and downstream signaling through the TrkB receptor are required for memory formation in both appetitive and aversive domains.

Chronic stress produces enduring decreases in novel stress-evoked c-fos mRNA expression in discrete brain regions of the rat.

Chronic stress produces numerous adaptations within the hypothalamic-pituitary-adrenal (HPA) axis that persist well after cessation of chronic stress. We previously demonstrated profound attenuation of HPA axis responses to novel environment 4-7 days following chronic stress. The present study tests the hypothesis that this HPA axis hyporesponsivity is associated with reductions in stress-evoked c-fos mRNA expression, a marker of neuronal activation, in discrete brain regions. Adult male Sprague-Dawley rats underwent 1 week of chronic variable stress (CVS), with unhandled rats serving as controls. Independent groups of control and CVS rats were exposed to novel environment at 16 h, 4 days, 7 days, or 30 days after CVS. Marked reductions of c-fos mRNA expression in the CVS group persisted for at least 30 days within the paraventricular nucleus of the hypothalamus, and for at least 1 week in rostroventrolateral septum and lateral hypothalamus. Lower levels of c-fos mRNA expression were observed at 16 h recovery in the ventrolateral medial preoptic area, basolateral amygdala, anterior cingulate cortex, and prelimbic cortex. The results demonstrate long-term alterations in neuronal activation within neurocircuits critical for regulation of physiological and psychological responses to stressors.

High prevalence of current asthma and active smoking effect among the elderly.

BACKGROUND: Although asthma is a common cause of morbidity in adults, relatively few objectively measured population studies of asthma prevalence in adult populations have been conducted. OBJECTIVE: To evaluate the prevalence of asthma, based on both a questionnaire and methacholine bronchial provocation test, and to determine the risk factors of asthma prevalence in an adult population. METHODS: A total of 2,467 adults, who were randomly selected from metropolitan urban, non-metropolitan urban and rural areas, responded to the modified ISAAC questionnaire, and underwent methacholine bronchial provocation tests and skin prick tests to locally common aeroallergens. RESULTS: The prevalence of current asthma based on the questionnaire and the methacholine challenge was 2.0% in adults younger than 40, 3.8% in 40- to 54-year-olds, 7.7% in 55- to 64-year-olds and 12.7% in those aged 65 or higher. For subjects of 55-64 years, active smoking was found to be significantly related with the prevalence of current asthma and bronchial hyper-responsiveness, although smoking was positively associated with percentage predictive value of forced expiratory volume of 1 s (FEV1). CONCLUSION: The prevalence of current asthma is common among the elderly, and active smoking may play an important role in the development of asthma and bronchial hyper-responsiveness among the elderly.

Increased levels of circulating autoantibodies to cultured human bronchial epithelial cell in adult patients with nonatopic asthma.

The pathogenetic mechanism of nonatopic asthma has not yet been defined. The idea of a possible involvement of autoimmunity in the pathogenesis of nonatopic asthma has been proposed by earlier studies. To evaluate the possible involvement of autoimmune response against bronchial epithelial cell in the pathogenesis of nonatopic asthma, we measured circulating autoantibodies to cultured human bronchial epithelial cell (BEAS-2B cell line) using enzyme-linked immunosorbent assay. We used stored serum samples form 38 age-matched healthy controls, 26 adult patients with atopic asthma, 16 adult patients with nonatopic asthma, and 12 adult patients with systemic lupus erythematosus. Levels of IgG autoantibodies to bronchial epithelial cell were significantly higher in patients with nonatopic asthma (mean+/-SD of absorbance values; 0.135+/-0.030) and systemic lupus erythematosus (0.293+/-0.181) than in healthy controls (0.112+/-0.016) and patients with atopic asthma (0.116+/-0.031) (p<0.05). This study showed that levels of circulating IgG autoantibodies to bronchial epithelial cell were increased in adult patients with nonatopic asthma. Further studies are needed to evaluate the possible involvement of autoimmune mechanism in the pathogenesis of nonatopic asthma.

Effect of endoscopic sinus surgery on asthmatic patients with chronic rhinosinusitis.

There have been several reports on the effectiveness of endoscopic sinus surgery (ESS) in asthmatic patients with chronic rhinosinusitis. Whether ESS has a positive effect on the clinical course of asthma still remains controversial. There have been several subjective evaluations but few objective results. We performed a study to evaluate the effectiveness of ESS in 19 patients with asthma who underwent ESS for rhinosinusitis. The use of antiasthma medication and postoperative asthma symptoms was analyzed. Objective changes of pulmonary function tests were evaluated. There was a significant improvement in diurnal and nocturnal asthma symptoms. Improvements in asthma medication scores were also confirmed, and individual asthma symptoms (dyspnea, cough, wheezing, and sputum production) improved significantly. Despite a reduction in use of antiasthma medication after ESS, the parameters of the pulmonary function tests did not change. Both subjectively and objectively, it seems that ESS, when used to treat asthmatic patients with chronic rhinosinusitis, can play a significant role in the clinical improvement of asthma.

Transient exposure of human bronchial epithelial cells to cytokines leads to persistent increased expression of ICAM-1.

Effects of several cytokines on kinetics of Intercellular Adhesion Molecule-1 (ICAM-1) and Vascular Cell Adhesion Molecule-1 (VCAM-1) expression were studied on a bronchial epithelial cell line (BEAS-2B). VCAM-I was neither constitutively expressed on BEAS-2B cells nor induced by Interferon-gamma (IFN-gamma). Tumor Necrosis Factor-alpha (TNF-alpha), Interleukin-1beta (IL-1beta), IFN-alpha, IL-4, IL-6, IL-8 or Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF). ICAM-1 was constitutively expressed on BEAS-2B cells. IFN-gamma and TNF-alpha upregulated ICAM-1 expression on these cells. The functional importance of IFN-gamma plus TNF-a upregulation of ICAM-1 expression on BEAS-2B cells was demonstrated by neutrophil-BEAS-2B cell adhesion assays. Cytokines are rapidly released and cleared in animals. Therefore, transient cytokine(s) exposure might occur on the bronchial mucosa. Brief incubation of BEAS-2B cells with IFN-gamma plus TNF-alpha led initial upregulation of ICAM-1 expression followed by a protracted downregulation. Our findings stress the importance of studying the mechanism(s) controlling the persistent increased expression of ICAM-1 after brief cytokine(s) exposure.

Grain dust induces IL-8 production from bronchial epithelial cells: the effect of dexamethasone on IL-8 production.

BACKGROUND: Recent publications have suggested an active participation of neutrophils to induce bronchoconstriction after inhalation of grain dust (GD). OBJECTIVE: To further understand the role of neutrophils in the pathogenesis of GD-induced asthma, this investigation was designed to determine whether human bronchial epithelial cells could produce IL-8 production and to observe the effect of dexamethasone on IL-8 production. MATERIALS AND METHODS: We cultured Beas-2B, a bronchial epithelial cell line. To observe GD-induced responses, four concentrations (1 to 200 microg/mL) of GD were incubated for 24 hours and compared with those without incubation of GD. To evaluate the effect of pro-inflammatory cytokines on IL-8 production, epithelial cells were incubated with peripheral blood mononuclear cell (PBMC) culture supernatant, which was derived from the culture of PBMC from a GD-induced asthmatic subject under the exposure to 10 microg/mL of GD, and compared with those cultured without addition of PBMC supernatant. The level of released IL-8 in the supernatant was measured by enzyme-linked immunosorbent assay. To evaluate the effect of dexamethasone on IL-8 production, four concentrations (5 to 5000 ng/mL) of dexamethasone were pre-incubated for 24 hours and the same experiments were repeated. RESULTS: There was significant production of IL-8 from bronchial epithelial cells with additions of GD in a dose-dependent manner (P < .05), which was significantly augmented with additions of PBMC supernatant (P < .05) at each concentration. Compared with the untreated sample, pretreatment of dexamethasone could induced a remarkable inhibitions (15% to 55%) of IL-8 production from bronchial epithelial cells in a dose-dependent manner. CONCLUSION: These results suggest that IL-8 production from bronchial epithelial cells may contribute to neutrophil recruitment occurring in GD-induced airway inflammation. The downregulation of IL-8 production by dexamethasone from bronchial epithelial cells may contribute to the efficacy of this compound in reducing cellular infiltration and ultimately to its anti-inflammatory property.

Occupational asthma and IgE sensitization to cellulase in a textile industry worker.

BACKGROUND: Although there have been a few reports of occupational asthma due to cellulase in several occupational settings, this is the first case of cellulase-induced occupational asthma in an employee working in the textile industry. Its pathogenetic mechanism remains to be further clarified. OBJECTIVE: It is important to alert physicians to the possibility of occupational asthma caused by cellulase in workers of the textile industry. METHODS AND RESULTS: The patient had atopy and strong positive responses to cellulase extract on skin prick tests. Bronchoprovocation test showed an early asthmatic response to cellulase extract. Serum specific IgE and specific IgG4 antibodies to cellulase were detected by enzyme-linked immunosorbent assay (ELISA). In order to further characterize the allergenic component of the extract, sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and electroblotting studies were performed. Eight IgE binding components ranging from 6 to 97.5 kD were detected within the cellulase extract. CONCLUSION: These findings suggest that inhalation of cellulase can induce IgE-mediated bronchoconstrictions in employees working in the textile industry.

Neuropeptides and asthma.

Although asthma is considered to be an inflammatory disease of the airways, neural mechanisms remain very important. Neural control of airways is far more complex than has been previously recognized. In addition to the classic neural pathways, the nonadrenergic, noncholinergic pathway has been described in the airways of animals and humans. Neuropeptides are present in sensory, parasympathetic, and sympathetic neurons in airways, and have been shown to have proinflammatory effects, such as increased mucus production, microvascular leakage, and smooth muscle contraction. Neuropeptides released from sensory nerves (eg, neurokinin A and substance P) mediate excitatory nonadrenergic, noncholinergic transmission, which causes bronchoconstriction and, possibly, bronchial hyperresponsiveness. Better understanding of neural mechanisms might provide a useful therapeutic approach in the future.

The spectrum of eosinophilic lung disease: radiologic findings.

PURPOSE: Eosinophilic lung disease includes various disease entities. Each disease manifests different radiologic findings. The purpose of this review is to present the radiologic findings of the spectrum of eosinophilic lung disease. METHOD: We reviewed the radiologic, histologic, and clinical findings of the spectrum of eosinophilic lung disease from the previous reports and our experiences. RESULTS: Simple pulmonary eosinophilia is characterized by transient and migrating opacities on chest radiography. Acute eosinophilic pneumonia is characterized by acute clinical symptoms and signs and rapid changes of radiographic diffuse reticular lesions. Chronic eosinophilic pneumonia, with more prolonged symptom duration, history of asthma, occurrence of relapse, and radiologic features of subpleural consolidation, can be differentiated from acute eosinophilic pneumonia. Allergic bronchopulmonary aspergillosis presents with bilateral central bronchiectasis with or without mucoid impaction. Although these diseases show specific radiographic findings, some show overlapping radiographic features. High-resolution CT enables characterization of parenchymal lesions further by showing internal and marginal features and the exact extent of the lesions. Extrapulmonary organs are involved in Churg-Strauss syndrome and idiopathic hypereosinophilic syndrome. Asthma is associated with Churg-Strauss syndrome, allergic bronchopulmonary aspergillosis, chronic eosinophilic pneumonia, and bronchocentric granulomatosis. CONCLUSION: Integration of clinical, laboratory, and radiologic findings enables initial and differential diagnoses of various eosinophilic lung diseases.

Pathological changes according to the severity of asthma.

BACKGROUND: There have been many studies concerning pathological changes in bronchial mucosa from asthmatics; however, few studies has been carried out to evaluate pathological changes according to the severity of asthma. OBJECTIVE: This study was designed to evaluate the cellular components in bronchoalveolar lavage fluid (BALF) and histological abnormalities in asthmatics according to the severity of asthma. METHODS: Bronchoalveolar lavages, bronchoscopic biopsies and ultrastructural examinations were performed in 13 asthmatics and 11 (BAL) or four (biopsies) non-asthmatic controls. The proportions of epithelial cells and correlations with PC20Meth which reflects bronchial hyperresponsiveness. Light microscopic examination revealed loss of epithelium, inflammatory cell infiltrations and thickening of the basement membrane which also showed significant correlation with PC20Meth. Hypertrophy of airway smooth muscles and hyperplasia of mucous glands were prominent in asthmatics but there was no difference according to the severity of asthma. Ultrastructural examination revealed that basement membrane thickening on light microscopic examination is due to the increased subepithelial collagen deposition with normal thickness of basal lamina. CONCLUSION: These data suggest that loss of epithelial cells, infiltration of inflammatory cells, especially eosinophils, and increased deposition of subepithelial collagen play major roles in determining the severity of asthma and non-specific bronchial hyperresponsiveness.

Ototoxicity of salicylate, nonsteroidal antiinflammatory drugs, and quinine.

Salicylates and most NSAIDS in high doses cause mild to moderate temporary hearing loss, either flat or greater in the high frequencies. Hearing loss is accompanied by tinnitus and suprathreshold changes. Salicylates may or may not exacerbate hearing loss and cochlear damage induced by noise. The mechanism of salicylate ototoxicity seems to be multifactorial. Morphologic studies suggest that no permanent cochlear damage occurs with salicylate ototoxicity. Electrophysiologic, morphologic, and in vitro data conclusively demonstrate that salicylate affects outer hair cells. In addition, salicylates appear to decrease cochlear blood flow. Salicylates and NSAIDs inhibit PG-forming cyclooxygenase, and recent studies suggest that abnormal levels of arachidonic acid metabolites consisting of decreased PGs and increased LTs may mediate salicylate ototoxicity. As with salicylate, quinine ototoxicity appears to be multifactorial in origin. The mechanism includes vasoconstriction and decreases in cochlear blood flow, as measured by laser Doppler flowmetry, motion photographic studies, and histologic studies. Reversible alterations of outer hair cells also appear to play an important role, as demonstrated by histology, electron microscopy, isolated hair cell studies, and cochlear potential evaluations. Unlike with salicylate, however, the role of prostaglandins in quinine ototoxicity has not been clearly demonstrated. Also, one of quinine's principal actions, antagonism of calcium-dependent potassium channels, has yet to be investigated for its potential role in ototoxicity.