Adipose tissue in the small airways: How much is enough to drive functional changes?

Obesity is a contributing factor to asthma severity; while it has long been understood that obesity is related to greater asthma burden, the mechanisms though which this occurs have not been fully elucidated. One common explanation is that obesity mechanically reduces lung volume through accumulation of adipose tissue external to the thoracic cavity. However, it has been recently demonstrated that there is substantial adipose tissue within the airway wall itself, and that the presence of adipose tissue within the airway wall is related to body mass index. This suggests the possibility of an additional mechanism by which obesity may worsen asthma, namely by altering the behaviour of the airways themselves. To this end, we modify Anafi & Wilson's classic model of the bistable terminal airway to incorporate adipose tissue within the airway wall in order to answer the question of how much adipose tissue would be required in order to drive substantive functional changes. This analysis suggests that adipose tissue within the airway wall on the order of 1%-2% of total airway cross-sectional area could be sufficient to drive meaningful changes, and further that these changes may interact with volume effects to magnify the overall burden.

Detailed characterization and impact of small airway dysfunction in school-age asthma.

BACKGROUND: Small airway dysfunction (SAD) is increasingly recognized as an important feature of pediatric asthma yet typically relies on spirometry-derived FEF25-75 to detect its presence. Multiple breath washout (MBW) and oscillometry potentially offer improved sensitivity for SAD detection, but their utility in comparison to FEF25-75, and correlations with clinical outcomes remains unclear for school-age asthma. We investigated SAD occurrence using these techniques, between-test correlation and links to clinical outcomes in 57 asthmatic children aged 8-18 years. METHODS: MBW and spirometry abnormality were defined as z-scores above/below ± 1.96, generating MBW reference equations from contemporaneous controls (n = 69). Abnormal oscillometry was defined as > 97.5th percentile, also from contemporaneous controls (n = 146). Individuals with abnormal FEF25-75, MBW, or oscillometry were considered to have SAD. RESULTS: Using these limits of normal, SAD was present on oscillometry in 63% (resistance at 5-20 Hz; R5-R20; >97.5th percentile), on MBW in 54% (Scond; z-scores> +1.96) and in spirometry FEF25-75 in 44% of participants (z-scores< -1.96). SAD, defined by oscillometry and/or MBW abnormality, occurred in 77%. Among those with abnormal R5-R20, Scond was abnormal in 71%. Correlations indicated both R5-R20 and Scond were linked to asthma medication burden, baseline FEV1 and reversibility. Additionally, Scond correlated with FENO and magnitude of bronchial hyper-responsiveness. SAD, detected by oscillometry and/or MBW, occurred in almost 80% of school-aged asthmatic children, surpassing FEF25-75 detection rates. CONCLUSIONS: Discordant oscillometry and MBW abnormality suggests they reflect different aspects of SAD, serving as complementary tools. Key asthma clinical features, like reversibility, had stronger correlation with MBW-derived Scond than oscillometry-derived R5-R20.

NLRP12 attenuates ozone-induced pulmonary inflammation by regulating canonical NF-κB Pathway.

Ozone (O3) is an important urban air pollutant having strong correlations with respiratory diseases. Several lines of evidence suggest that O3 exposure causes airway hyperresponsiveness (AHR) and pulmonary inflammation. Inhibitory innate immune receptors, such as NLRP12, have been demonstrated to alleviate inflammation, but the functional role for NLRP12 in O3-induced lung inflammatory inflammation remains to be reported. Here, we determined whether NLRP12 took a protective role in O3-induced AHR and pulmonary inflammation via the suppression of canonical NF-κB. C57BL/6 J mice were exposed to filtered air (FA) or 0.25, 0.50 and 1.00 ppm (3 h/day for 5 consecutive days) followed by detection of airway resistance, white blood cells, total proteins, and cytokines. Meanwhile, NLRP12 in lung tissue were detected by real time PCR. Moreover, we also examined protein expression of NLRP12 and key biomarkers of NF-κB pathway. It was shown that 24 h post O3 exposure, AHR as wells as total cells, proteins, and cytokines contents in BALF of mice were increased compare to those of FA controls in a dose-dependent manner. Notably, O3-induced AHR and lung inflammation were associated with significant decrease in pulmonary NLRP12 and upregulation of phosphorylated IRAK1, p65 and IκBα in canonical NF-κB pathway. Intratracheal administration of NLRP12-overexpresing adenovirus 4 days prior to O3 exposure alleviated AHR and lung inflammation, and inhibited canonical NF-κB pathway activation. The findings from this study indicate that NLRP12 attenuates O3-induced AHR and pulmonary inflammation, possibly through regulating canonical NF-κB pathway. This provides a novel target for the prevention and treatment of lung diseases induced by O3 exposure.

Wheeze is an unreliable endpoint for bronchial methacholine challenges in preschool children.

BACKGROUND: Onset of wheeze is the endpoint often used in the determination of a positive bronchial challenge test (BCT) in young children who cannot perform spirometry. We sought to assess several clinical endpoints at the time of a positive BCT in young children with recurrent wheeze compared to findings in school-aged children with asthma. METHODS: Positive BCT was defined in: (1) preschool children (n = 22) as either persistent cough, wheeze, fall in oxygen saturation (SpO2 ) of ≥5%, or ≥50% increase in respiratory rate (RR) from baseline; and (2) school-aged children (n = 22) as the concentration of methacholine (MCh) required to elicit a 20% decline in FEV1 (PC20 ). RESULTS: All preschool children (mean age 3.4 years) had a positive BCT (median provocative MCh concentration 1.25 mg/ml [IQR, 0.62, 1.25]). Twenty (91%) school-aged children (mean age 11.3 years) had a positive BCT (median PC20 1.25 mg/ml [IQR, 0.55, 2.5]). At the time of the positive BCT, the mean fall in SpO2 (6.9% vs. 3.8%; p = .001) and the mean % increase in RR (61% vs. 22%; p < .001) were greater among preschool-aged than among school-aged children. A minority of children developed wheeze at time of positive BCT (23% preschool- vs. 15% school-aged children; p = .5). CONCLUSIONS: The use of wheeze as an endpoint for BCT in preschool children is unreliable, as it rarely occurs. The use of clinical endpoints, such as ≥25% increase in RR or fall in SpO2 of ≥3%, captured all of our positive BCT in preschool children, while minimizing undue respiratory distress.

Hyper-responsiveness to warfarin in a young patient with the VKORC1 -1639GA/CYP2C9*1*46 genotype: a case report.

BACKGROUND: Warfarin is the most widely used oral anticoagulant; nevertheless, dosing of warfarin is problematic for clinicians worldwide. Inter-individual variability in response to warfarin is attributed to genetic as well as non-genetic factors. Pharmacogenomics studies have identified variants in CYP2C9 and VKORC1 genes as significant predictors of warfarin dose, however, phenotypes of rare variants are not well characterized. CASE PRESENTATION: We report a case of hyper-responsiveness to warfarin in a 22-year-old outpatient with Crohn's disease who presented with a swollen, red, and painful left calf. Deep venous thrombosis (DVT) in the left lower extremity was confirmed via ultrasonography, and hence, anticoagulation therapy of heparin and concomitant warfarin was initiated. Warfarin dose of 7.5 mg/day was estimated by the physician based on clinical factors. Higher than the expected international normalized ratio (INR) value of 4.5 necessitated the reduction of the warfarin dose to 5 and eventually to 2.5 mg/day to reach a therapeutic INR value of 2.6. Pharmacogenetic profiling of the VKORC1 -1639G > A and CYP2C9 *2, *3, *4, *5, *8, *14, *20, *24, *26, *33, *40, *41, *42, *43, *45, *46, *55, *62, *63, *66, *68, *72, *73 and *78 revealed a VKORC1-1639GA/CYP2C9*1*46 genotype. The lower catalytic activity of the CYP2C9*46 (A149T) variant was previously reported in in vitro settings. CONCLUSIONS: This is the first report on a case of warfarin hyper-responsive phenotype of a patient with the heterozygous CYP2C9*1*46 polymorphism.

Sophoraflavanone G from Sophora flavescens Ameliorates Allergic Airway Inflammation by Suppressing Th2 Response and Oxidative Stress in a Murine Asthma Model.

Sophoraflavanone G (SG), isolated from Sophora flavescens, has anti-inflammatory and anti-tumor bioactive properties. We previously showed that SG promotes apoptosis in human breast cancer cells and leukemia cells and reduces the inflammatory response in lipopolysaccharide-stimulated macrophages. We investigated whether SG attenuates airway hyper-responsiveness (AHR) and airway inflammation in asthmatic mice. We also assessed its effects on the anti-inflammatory response in human tracheal epithelial cells. Female BALB/c mice were sensitized with ovalbumin, and asthmatic mice were treated with SG by intraperitoneal injection. We also exposed human bronchial epithelial BEAS-2B cells to different concentrations of SG to evaluate its effects on inflammatory cytokine levels. SG treatment significantly reduced AHR, eosinophil infiltration, goblet cell hyperplasia, and airway inflammation in the lungs of asthmatic mice. In the lungs of ovalbumin-sensitized mice, SG significantly promoted superoxide dismutase and glutathione expression and attenuated malondialdehyde levels. SG also suppressed levels of Th2 cytokines and chemokines in lung and bronchoalveolar lavage samples. In addition, we confirmed that SG decreased pro-inflammatory cytokine, chemokine, and eotaxin expression in inflammatory BEAS-2B cells. Taken together, our data demonstrate that SG shows potential as an immunomodulator that can improve asthma symptoms by decreasing airway-inflammation-related oxidative stress.

Therapeutic Efficacy of Weissella cibaria CMU and CMS1 on Allergic Inflammation Exacerbated by Diesel Exhaust Particulate Matter in a Murine Asthma Model.

Background and Objectives: Diesel exhaust particulate matter (DEPM) is an air pollutant that is associated with asthma. In this study, the therapeutic efficacy of Weissella cibaria strains CMU (Chonnam Medical University) and CMS (Chonnam Medical School) 1, together with the drug Synatura, an anti-tussive expectorant, was investigated in a murine asthma model exacerbated by DEPM. Materials and Methods: BALB/c mice were sensitized with ovalbumin (OVA) before intranasal challenge with OVA and DEPM. W. cibaria CMU, CMS1, and Synatura were administered orally for 21 days. Results: Neither Synatura nor W. cibaria strains affected spleen, liver, or lung weights. W. cibaria strains CMU and CMS1 significantly reduced the levels of interleukin (IL)-4, OVA-specific immunoglobulin E (IgE), and total lung collagen in bronchoalveolar lavage fluid (BALF), similar to those with Synatura, regardless of the oral dose concentration (p < 0.05). In addition, the W. cibaria CMU strain significantly alleviated IL-1ß, IL-6, IL-12, monocyte chemotactic protein-1, and tumor necrosis factor-α in BALF, whereas the CMS1 strain significantly alleviated IL-10 and IL-12 in BALF (p < 0.05); however, Synatura did not show any statistical efficacy against them (p > 0.05). All concentrations of W. cibaria CMU and low concentrations of W. cibaria CMS1 significantly reduced lung bronchiolar changes and inflammatory cell infiltration. Conclusions: In conclusion, W. cibaria CMU in asthmatic mice showed better efficacy than W. cibaria CMS1 in improving asthma exacerbated by DEPM exposure, as well as better results than pharmaceuticals.

Cellular clocks in hyperoxia effects on [Ca2+]i regulation in developing human airway smooth muscle.

Supplemental O2 (hyperoxia) is necessary for preterm infant survival but is associated with development of bronchial airway hyperreactivity and childhood asthma. Understanding early mechanisms that link hyperoxia to altered airway structure and function are key to developing advanced therapies. We previously showed that even moderate hyperoxia (50% O2) enhances intracellular calcium ([Ca2+]i) and proliferation of human fetal airway smooth muscle (fASM), thereby facilitating bronchoconstriction and remodeling. Here, we introduce cellular clock biology as a novel mechanism linking early oxygen exposure to airway biology. Peripheral, intracellular clocks are a network of transcription-translation feedback loops that produce circadian oscillations with downstream targets highly relevant to airway function and asthma. Premature infants suffer circadian disruption whereas entrainment strategies improve outcomes, highlighting the need to understand relationships between clocks and developing airways. We hypothesized that hyperoxia impacts clock function in fASM and that the clock can be leveraged to attenuate deleterious effects of O2 on the developing airway. We report that human fASM express core clock machinery (PER1, PER2, CRY1, ARNTL/BMAL1, CLOCK) that is responsive to dexamethasone (Dex) and altered by O2. Disruption of the clock via siRNA-mediated PER1 or ARNTL knockdown alters store-operated calcium entry (SOCE) and [Ca2+]i response to histamine in hyperoxia. Effects of O2 on [Ca2+]i are rescued by driving expression of clock proteins, via effects on the Ca2+ channels IP3R and Orai1. These data reveal a functional fASM clock that modulates [Ca2+]i regulation, particularly in hyperoxia. Harnessing clock biology may be a novel therapeutic consideration for neonatal airway diseases following prematurity.

Ginsenoside Rh1 attenuates ovalbumin-induced asthma by regulating Th1/Th2 cytokines balance.

Ginsenoside Rh1 (Rh1) has anti-inflammatory effects in asthma mice, but the underlying mechanism remains unclear. BALB/c mice were sensitized and challenged with ovalbumin (OVA) to construct asthma model. Mice received Rh1 or tiotropium bromide 0.5 h before OVA challenge. Airway morphology and airway remodeling were assessed by HE staining and Masson's trichrome staining, respectively. Th1/Th2 cytokines in serum or broncho alveolar lavage fluid (BALF) were measured by ELISA kits. Rh1 significantly alleviated the lung resistance and airway resistance, and reduced the number of total inflammation cells, eosinophils, neutrophils, and lymphocytes in BALF of the asthmatic mice. The morphological changes and collagen deposition of airway were also reduced by Rh1 in asthmatic mice. The increase of Eotaxin, IL-4, IL-5, IL-13, and IL-33 and the decrease of IL-12 and IFN-γ in both BALF and serum of OVA exposed mice were reversed by Rh1. Rh1 attenuates OVA-induced asthma in the mice model by regulating Th1/Th2 cytokines balance.

Small airway dysfunction in patients with cough variant asthma: a retrospective cohort study.

BACKGROUND: Cough variant asthma (CVA) is one of the special populations of asthma. The aim of the study was to compare small airways, the degree of bronchial hyperresponsiveness (BHR) and airway inflammatory subtypes between CVA and classic asthma (CA), and investigate the relationship between these markers to determine the accuracy as indicators of CVA. METHODS: A total of 825 asthmatic patients participated in the study and 614 were included. 614 patients underwent spirometry and a bronchial challenge with methacholine and 459 patients performed induction sputum cell test. RESULTS: The number of CVA patients showed less small airway dysfunction than those of CA patients (p < 0.005). The degree of small airways dysfunction was higher in the CA group compared with the CVA group (p < 0.001). Small airways dysfunction was severer in the eosinophilic airway inflammatory subtype compared with other subtypes (p < 0.05).The area under curve of MMEF, FEF50 and FEF75 (% predicted) was 0.615, 0.621, 0.606, respectively. 0.17mcg of PD20 and 4.7% of sputum eosinophils was the best diagnostic value for CVA with an AUC of 0.582 and 0.575 (p = 0.001 and p = 0.005, respectively). CONCLUSIONS: The eosinophilic airway inflammatory subtype may be increased small airway dysfunction. The value of small airways, BHR and induction sputum cells in CVA prediction, which reflected significant, but not enough to be clinically useful.

Connection between Periodontitis-Induced Low-Grade Endotoxemia and Systemic Diseases: Neutrophils as Protagonists and Targets.

Periodontitis is considered a promoter of many systemic diseases, but the signaling pathways of this interconnection remain elusive. Recently, it became evident that certain microbial challenges promote a heightened response of myeloid cell populations to subsequent infections either with the same or other pathogens. This phenomenon involves changes in the cell epigenetic and transcription, and is referred to as ''trained immunity''. It acts via modulation of hematopoietic stem and progenitor cells (HSPCs). A main modulation driver is the sustained, persistent low-level transmission of lipopolysaccharide from the periodontal pocket into the peripheral blood. Subsequently, the neutrophil phenotype changes and neutrophils become hyper-responsive and prone to boosted formation of neutrophil extracellular traps (NET). Cytotoxic neutrophil proteases and histones are responsible for ulcer formations on the pocket epithelium, which foster bacteremia and endoxemia. The latter promote systemic low-grade inflammation (SLGI), a precondition for many systemic diseases and some of them, e.g., atherosclerosis, diabetes etc., can be triggered by SLGI alone. Either reverting the polarized neutrophils back to the homeostatic state or attenuation of neutrophil hyper-responsiveness in periodontitis might be an approach to diminish or even to prevent systemic diseases.

Predictors of Clopidogrel Hyper-Responsiveness in Neuro-Interventional Procedures.

BACKGROUND: Hyper-responsiveness to clopidogrel abnormally inhibits platelet aggregation and increases hemorrhagic complications. The present study investigated clinical factors related to clopidogrel hyper-responsiveness in neuro-interventional procedures. METHODS: Two hundred twenty-four patients receiving clopidogrel for coil embolization to treat unruptured cerebral aneurysm or carotid artery stenting to treat carotid artery stenosis at the internal carotid artery origin were retrospectively reviewed for their P2Y12 reactivity unit (PRU) values and clinical characteristics. Hyper-responsiveness to clopidogrel was defined as a PRU of <95. RESULTS: The mean PRU was 218.2 ± 77.8. Hyper-responsiveness to clopidogrel was observed in 12 patients (5.4%). Hyper-responsiveness was observed in younger patients, patients with a lower concentration of hemoglobin A1c, and patients with a higher low-density lipoprotein cholesterol (LDL-C) concentration compared with non-hyper-responsive patients (P = 0.01, P < 0.01, P < 0.01, respectively). On analysis of concomitant drugs, the patients in the hyper-responsive group were less frequently administered calcium channel blockers (CCBs) compared with the non-hyper-responsive group (P = 0.01). No significant differences in the usage of proton pump inhibitors or statins were observed. A LDL-C concentration of >120 mg/dL and no usage of CCBs were significant independent predictors of hyper-responsiveness to clopidogrel with a multivariate analysis (OR; 6.16, 95% CI, 1.57-26.64, P = 0.01, OR; 0.09, 95% CI, 0.01-0.82, P = 0.03, respectively). CONCLUSION: The present study shows that a higher LDL-C concentration and no usage of CCBs are independent predictors of clopidogrel hyper-responsiveness. These results are useful to predict perioperative hemorrhagic complications. Considering dose reduction of clopidogrel or alternative drugs in high risk cases is necessary to prevent perioperative hemorrhagic complications.

Phenotype- and patient-specific modelling in asthma: Bronchial thermoplasty and uncertainty quantification.

Theoretical models can help to overcome experimental limitations to better our understanding of lung physiology and disease. While such efforts often begin in broad terms by determining the effect of a disease process on a relevant biological output, more narrowly defined simulations may inform clinical practice. Two such examples are phenotype-specific and patient-specific models, the former being specific to a group of patients with common characteristics, and the latter to an individual patient, in view of likely differences (heterogeneity) between patients. However, in order for such models to be useful, they must be sufficiently accurate, given the available data about the specific characteristics of the patient. We show that, for asthma in particular, this approach is promising: phenotype-specific targeting may be an effective way of selecting patients for treatment based on their airway remodelling phenotype, and patient-specific targeting may be viable with the use of a clinically-plausible dataset. Specifically we consider asthma and its treatment by bronchial thermoplasty, in which the airway smooth muscle layer is directly targeted by thermal energy. Patient-specific and phenotype-specific models in this context are considered using a combination of biobank data from ex vivo tissue samples, CT imaging, and optical coherence tomography which allows more detailed resolution of the airway wall structures.

Predictive value of childhood airway hyper-responsiveness to indirect stimuli: 10-year longitudinal study.

BACKGROUND: Airway hyper-responsiveness (AHR) is a common feature in asthma. The use of AHR in predicting active asthma or the persistence of AHR in childhood is poorly understood. By analyzing longitudinal connections including different measures of AHR, lung function, and inflammation markers, we sought to identify the best available method for predicting persistence of AHR and identification of later active asthma. METHODS: We tested 105 asthmatic children aged 3-7 years with fractional exhaled nitric oxide (FeNO), impulse oscillometry (IOS), and AHR evaluated by indirect methods (hypertonic saline and exercise challenge). Ten years later, 64 children participated in the follow-up visit and were tested with FeNO, IOS, spirometry, and methacholine challenge. At both study visits, blood samples were collected, and a questionnaire was completed. RESULTS: Asthma was in remission in 66% of patients at adolescence. AHR measured by hypertonic saline challenge at preschool age was associated with asthma symptoms (OR 10.2; 95% CI 2.8, 37.3) but not with AHR estimated with methacholine challenge 10 years later. AHR measured by exercise challenge was not associated with AHR or recent asthma symptoms in adolescence. Preschool eosinophilia continued until adolescence in 87% of patients but was not associated with AHR or subjective signs of asthma 10 years later. Wheezy preschoolers with atopy had a higher risk for AHR in adolescence (OR 4.1; 95% CI 1.0, 16.2). CONCLUSION: Results from hypertonic saline challenge are associated with persistent asthma symptoms even after a decade. AHR measured by indirect methods at preschool age did not predict AHR in adolescence.

Effects of COX inhibitors on responsiveness of the tracheal tract to acetylcholine and histamine and their relationship with LTC4 and PGE2 levels of bronchoalveolar lavage fluid in allergic Guinea pigs.

Introduction: Nonsteroidal anti-inflammatory drugs (NSAIDs) intervene in the COX (cyclooxygenase) pathways which generate two important inflammation mediators, prostaglandins (PGs) and leukotriene (LTs). Contradictory claims regarding the effect of NSAIDs in asthmatic patients continues to be an issue. The present study investigated the effects of COX inhibitors on the responsiveness of the tracheal tract and on the levels of LTC4 and PGE2 in cells of the bronchoalveolar lavage fluid in an allergic guinea pig model.Materials and Methods: Adult male Dunkin-Hartley guinea pigs (250 - 300 g) were divided into seven groups of six animals each. Four COX inhibitors, aspirin (200 mg/kg and 20 mg/kg), indomethacin (10 mg/kg), ketoprofen (10 mg/kg), and celecoxib (25 mg/kg), were given orally on day 17 to allergy induced guinea pigs at 0, 12, and 24 h before ovalbumin challenge on day 18. PGF2 and LT4 were measured in the bronchoalveolar lavage fluid as well as inflammatory cell count and total protein. Tracheal responsiveness to acetylcholine (Ach) and histamine (His) also was evaluated.Results: An augment in the response of the trachea to Ach and His, as well as overt allergenic signs including short breath, wheezing and sneezing, was observed. The most significant increase in tracheal hyper-responsiveness was observed in the ketoprofen-treated group with similar but less pronounced changes observed in the indomethacin-treated group. Although some variables increased with the aspirin and celecoxib treatments, overall the tracheal sensitivity was reduced. Inflammatory cells including eosinophils and neutrophils corresponded to the changes observed for each treatment group.Conclusion: Ketoprofen and indomethacin increased the tracheal sensibility to Ach and His; therefore, their administration is not recommended in patients susceptible to allergy.

Downregulated Rac1 promotes apoptosis and inhibits the clearance of apoptotic cells in airway epithelial cells, which may be associated with airway hyper-responsiveness in asthma.

The accumulation of airway apoptotic cells may be an important factor causing airway hyper-responsiveness (AHR). Whether the apoptotic cells can be promptly removed is related to the occurrence and course of asthma. In recent years, studies have shown that Rac1 is involved in many cellular biological activities including the formation and elimination of apoptotic cells. In this study, based on the analysis of airway local cells and related factors in asthmatic mice, we evaluated the expression of Rac1 in airway epithelial cells or phagocytes and analysed its relationship with the incidence of apoptosis or scavenging of apoptotic cells. Our data showed that the expression level of Rac1 in asthmatic mice decreased significantly, while the expression of IL-33 increased obviously. The airway epithelial cell line was stimulated by curcumin at 50 µmol/L for 24-48 hours; more than 50% of the cells were apoptotic, and of which, about 20% were late apoptosis. Rac1 inhibitor (NSC23766) can enhance the apoptosis effect. In addition, the ability of phagocytosis and migration in the epithelial cells or macrophages was increased following the application of Rac1 inhibitors or specific siRNA in a dose-dependent manner, and the expression level of IL-33 was simultaneously increased after blocking Rac1. It is suggested that the down regulation of Rac1 in asthma may contribute to the apoptosis of airway epithelial cells and affect the clearance of apoptotic cells, which will lead to the aggregation of the apoptotic cells in the respiratory tract and participate in AHR.

Acetaminophen is both bronchodilatory and bronchoprotective in human precision cut lung slice airways.

Epidemiologic studies have demonstrated an association between acetaminophen (APAP) use and the development of asthma symptoms. However, few studies have examined relationships between APAP-induced signaling pathways associated with the development of asthma symptoms. We tested the hypothesis that acute APAP exposure causes airway hyper-responsiveness (AHR) in human airways. Precision cut lung slice (PCLS) airways from humans and mice were used to determine the effects of APAP on airway bronchoconstriction and bronchodilation and to assess APAP metabolism in lungs. APAP did not promote AHR in normal or asthmatic human airways ex vivo. Rather, high concentrations mildly bronchodilated airways pre-constricted with carbachol (CCh), histamine (His), or immunoglobulin E (IgE) cross-linking. Further, the addition of APAP prior to bronchoconstrictors protected the airways from constriction. Similarly, in vivo treatment of mice with APAP (200 mg/kg IP) resulted in reduced bronchoconstrictor responses in PCLS airways ex vivo. Finally, in both mouse and human PCLS airways, exposure to APAP generated only low amounts of APAP-protein adducts, indicating minimal drug metabolic activity in the tissues. These findings indicate that acute exposure to APAP does not initiate AHR, that high-dose APAP is protective against bronchoconstriction, and that APAP is a mild bronchodilator.

Clinical Characteristics of Severe Refractory Asthma Associated with the Effectiveness of Bronchial Thermoplasty.

We investigated the clinical characteristics of refractory asthma associated with the effectiveness of bronchial thermoplasty (BT). We retrospectively evaluated data from 10 patients who underwent BT between June 2016 and December 2017 at Okayama Medical Center. The following were measured before and 6 months post-BT: forced expiratory volume in 1.0 s (FEV1), fractional exhaled nitric oxide (FeNO), immunoglobulin E (IgE) level, blood eosinophil counts (Eosi), Asthma Quality of Life Questionnaire (AQLQ) score, and preventive medication use. At baseline, the mean post-bronchodilator FEV1 was 80.9% of the predicted value (range 45.6-115.7%). All patients were being treated with moderate- or high-dose inhaled corticosteroids and long-acting ß2 agonists. The AQLQ improved from 4.26±1.67 at baseline to 5.59±0.94 at 6 months post-BT (p<0.05). The %FEV1, FeNO, IgE, and Eosi did not change significantly between baseline and 6 months post-BT. No severe complications were reported. BT was effective for non-allergic and non-eosinophilic in 3 patients, and allergic or eosinophilic in 4 patients. Their AQLQ improved by > 0.5 points post-BT. For both allergic and eosinophilic asthmatics following mepolizumab, BT was not useful. BT was effective for non-allergic and non-eosinophilic or allergic asthmatics, but insufficient for both allergic and eosinophilic following mepolizumab.

Potential Mechanisms of T Cell-Mediated and Eosinophil-Independent Bronchial Hyperresponsiveness.

Bronchial asthma is a chronic disease characterized by reversible airway obstruction, mucus production, and bronchial hyperresponsiveness (BHR). Although Th2 cell-mediated eosinophilic inflammation is an important disease mechanism in the majority of patients with bronchial asthma, recent studies suggest the possible development of Th2-independent airway inflammation and BHR. These non-Th2 endotype patients seem to consist of multiple subgroups, and often do not respond to inhaled corticosteroids. Therefore, to understand the pathogenesis of asthma, it is important to characterize these non-Th2 subgroups. Recently, we demonstrated that Th9 cells induce eosinophil infiltration and eosinophil-independent BHR, and Th9 cells-mediated BHR may be resistant to glucocorticoid. In this review, we summarize the contribution of several T cell subsets in the development of bronchial asthma and introduce our recent study demonstrating Th9 cell-mediated and eosinophil-independent BHR.

Bronchial hyper-responsiveness in preterm-born subjects: A systematic review and meta-analysis.

BACKGROUND: Preterm-born survivors have increased respiratory symptoms and decreased lung function, but the nature of bronchial hyper-responsiveness (BHR) is unclear. We conducted a systematic review and meta-analysis for BHR in preterm-born survivors including those with and without chronic lung disease in infancy (CLD) comparing results to term-born subjects. METHODS: We searched eight databases up to December 2016. Included articles compared BHR in preterm-born and term-born subjects. Studies reporting BHR as decreases in forced expiratory volume in 1 second (FEV1 ) after provocation stimuli were included. The analysis used Review Manager V5.3. RESULTS: From 10 638 titles, 265 full articles were screened, and 28 included in a descriptive analysis. Eighteen articles were included in a meta-analysis as they reported the proportion of subjects who had BHR. Pooled odds ratio (OR) estimates (95% confidence interval) for BHR comparing the preterm and term-born groups was 1.88 (1.32, 2.66). The majority of the studies reported BHR after a methacholine challenge or an exercise test. Odds ratio was 1.89 (1.12, 3.19) after methacholine challenge and 2.59 (1.50, 4.50) after an exercise test. Nine of fifteen articles reporting BHR in CLD subjects were included in a meta-analysis. Differences for BHR including for methacholine (OR 4.35; 2.36, 8.03) and exercise (OR 5.13; 1.82, 14.47) were greater in the CLD group compared to the term group. CONCLUSIONS: Preterm-born subjects especially those who had CLD had increased rates of BHR to direct (methacholine) and indirect (exercise) stimuli compared to term-born subjects suggesting subgroups might benefit from anti-inflammatory or bronchodilator therapies.