Increased Airway Responsiveness Research Articles

Comparison of multi-wall carbon nanotube and nitrogen-doped multi-wall carbon nanotube effects on lung function and airway reactivity in rats

Incorporation of multi-wall carbon nanotubes (MWCNT) into materials has raised concerns about their potential hazards to manufacturing workers. In animal models, airway inflammation and lung fibrosis follow aspiration, instillation, and inhalation exposures to MWCNT. However, the effects of MWCNT on pulmonary function, airway reactivity and airway epithelium function following inhalation exposure has not been studied. We investigated whether inhaled MWCNT affects lung resistance (RL) and dynamic compliance (Cdyn), reactivity to inhaled methacholine (MCh), epithelial regulation of airway reactivity to MCh in vitro, and airway epithelial ion transport. Male rats were exposed by whole body inhalation for 6 h to air or aerosolized MWCNT (0.5, 1 or 5 mg/m3) for one or nine days. Eighteen h after 1 d exposure to 5 mg/m3 MWCNT, basal RL was increased and basal Cdyn was decreased; changes did not persist for 7 d. Reactivity to MCh (RL) was increased and Cdyn responses were decreased at 18 h, but not 7 d after exposure to 1 and 5 mg/m3 MWCNT. The effects of i.t.-instilled MWCNT and nitrogen-doped MWCNT (N-MWCNT) on pulmonary function and reactivity to MCh at doses comparable to deposition after inhalation of 5 mg/m3 at 1 d and 0.5, 1, and 5 mg/m3 MWCNT 9 d-exposures were compared. Both nanoparticles increased airway reactivity (RL); N-MWCNT did not affect Cdyn responses. Lung function and airway reactivity are altered following a single MWCNT inhalation and generally subside over time. Given i.t., MWCNT's and N-MWCNT's effects were comparable, but N-MWCNT evoke smaller changes in Cdyn responses.

Source-apportioned coarse particulate matter exacerbates allergic airway responses in mice

Exposure to coarse particulate matter (PM) is associated with lung inflammation and exacerbation of respiratory symptoms in sensitive populations, but the degree to which specific emission sources contribute to these effects is unclear. We examined whether coarse PM samples enriched with diverse sources differentially exacerbate allergic airway responses. Coarse PM was collected weekly (7/2009–6/2010) from urban (G.T. Craig [GTC]) and rural (Chippewa Lake Monitor [CLM]) sites in the Cleveland, Ohio area. Source apportionment results were used to pool GTC filter PM extracts into five samples dominated by traffic, coal, steel (two samples), or road salt sources. Five CLM samples were prepared from corresponding weeks. Control non-allergic and house dust mite (HDM)-allergic Balb/cJ mice were exposed by oropharyngeal aspiration to 100 μg coarse GTC or CLM, control filter extract, or saline only, and responses were examined 2 d after PM exposures. In allergic mice, CLM traffic, CLM road salt and all GTC samples except steel-1 significantly increased airway responsiveness to methacholine (MCh) compared with control treatments. In non-allergic mice, CLM traffic, CLM steel-2 and all GTC samples except coal significantly increased bronchoalveolar lavage fluid (BALF) neutrophils, while only CLM traffic PM increased eosinophils in allergic mice. In non-allergic mice, CLM coal PM increased BALF interleukin (IL)-13 and GTC steel-1 PM increased TNF-α levels. These results demonstrate that equal masses of GTC and CLM coarse PM enriched with a variety of sources exacerbate allergic airway disease. Greater PM concentrations at the urban GTC site signify a greater potential for human health effects.

Airway responsiveness to methacholine and incidence of COPD: an international prospective cohort study

BackgroundIt has been debated, but not yet established, whether increased airway responsiveness can predict COPD. Recognising this link may help in identifying subjects at risk.ObjectiveWe studied prospectively whether airway responsiveness...

Men are from Mars, Women are from Venus. Gender specific changes in pulmonary function in 1 year old rats after neonatal hyperoxia exposure

RationalePreterm birth affects about 11% of pregnancies worldwide. The Institute of Medicine estimated the cost associated with premature birth to be $36 billion in 2016. Lungs in preterm infants are in the critical saccular stage of lung development and susceptible to the oxygen‐induced chronic lung disease known as bronchopulmonary dysplasia (BPD). BPD is characterized by functional abnormalities including decreased saccular/alveolar septation, decreased microvascular cross‐sectional area with or without pulmonary hypertension, airway injury with or without increased airway reactivity, and abnormalities of control of breathing in various combinations. While the initial inflammation improves, chronic inflammation ensues for a long time. We tested how neonatal hyperoxia exposure affects lung function one year after birth. We postulated an increase in lung collagen levels reflected by reduced pulmonary function.Methods6 newborn male and female rats in each group were exposed to Hyperoxia (Hx; 85% O2) or Normoxia (Nx; 21% O2) for 14 days, then aged to 1 year in Nx. At one year, lung function was measured using a FlexiVent (Scireq, Montreal, Canada). Using a single frequency forced oscillation manoeuvre and a low‐frequency forced oscillation technique the lung was tested for compliance and resistance. Total lung collagen was determined by a colorimetric assay using Ehrlich's reagent.ResultsAnalysis of one year old rats showed no difference in weight and body length between the Nx and the Hx group within each gender. The inspiratory capacity (IC) was significantly higher in the Hx exposed male rats compared to the Nx exposed male rats (12.6±0.6 ml vs 14.0±0.9 ml; p=0.02). The difference in IC in female rats was significantly lower in the Hx group compared to the Nx group (11.3±0.4 vs 10.1±0.6 ml; p=0.002). Dynamic compliance was significantly increased in the male Hx group compared to the male Nx group (1.43±0.05 vs 1.61±0.11 ml/cm H2O; p=0.04). In contrast, the female Hx group showed significantly reduced compliance compared to the female Nx group (1.32±0.05 vs 1.15±0.17 ml/cm H2O). In addition, the PV loop area was higher in the male Hx group compared to the male Nx group and no difference was found between the two female groups. Total collagen in lung tissue was not different between the male Hx and Nx groups but was higher in the female Hx compared to the Nx group.ConclusionOne year after neonatal Hx exposure, the male lung shows increased compliance and inspiratory capacity compared to the Nx exposed rats suggesting a trend to emphysema. In contrast, female rats show signs of lung fibrosis reflected by reduced compliance and increased total collagen content. This data suggests that neonatal oxygen exposure initiates alterations in inflammatory and repair pathways that are different between male and female rats.Support or Funding InformationNHLBI: R01 HL115061‐01 (Eldridge)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Limonene‐induced Activation of A2A Adenosine Receptors Reduces Airway Inflammation and Reactivity in a Mouse Model of Asthma

Animal models of asthma have shown that limonene (terpene in citrus fruits) reduces inflammation and airway reactivity. However, the mechanism of these effects is unknown. We hypothesized that limonene activates A2A adenosine receptors (A2AAR) to produce its effects in asthma, after comparing Glide scores for limonene (−5.19) and A2AAR agonist CGS 21680 (−8.43). We investigated the effects of limonene on lung inflammation and airway responsiveness to methacholine (MCh) as well NECA (nonselective adenosine analog) in A2AAR knock‐out (A2AKO) and wild‐type (WT) mice. Mice were divided into control (CON) and allergen sensitized‐challenged (SEN) groups, and were sensitized i.p. on days 1, 6 with 20 μg ovalbumin (OVA) followed by 5% OVA aerosol challenges on days 11–13 (n=6 mice per group). Limonene was administered as an inhalation prior to allergen challenges in one group of allergic mice for both WT and KO (SEN+LIM). Whole body plethysmography (measuring airway responsiveness as enhanced pause, Penh) and bronchoalveolar lavage (BAL) studies were performed. Airway responsiveness to MCh (48 mg/ml) in WT SEN group was significantly lowered with limonene treatment (420±92.57% in SEN vs. 56.23±25% in SEN+LIM). However, limonene did not have an effect in A2AKO (553±85% in SEN vs. 588±34% in SEN+LIM). NECA‐induced increased airway responsiveness was attenuated in limonene‐treated WT SEN mice (1002±161 in SEN vs. 250±226%, p<0.05) while no effect was observed in A2AKO groups (541±44% in SEN vs. 528±147% in SEN+LIM). Differential BAL cell analysis showed that limonene reduced levels of eosinophils in WT SEN (70.66±2.6% in SEN vs. 28.66±1.45% in SEN+LIM, p<0.05) while no difference was observed in A2AKO (76.33±1.35% in SEN vs 79±0.69% in SEN+LIM). These data suggest that limonene‐induced reduction in airway inflammation and airway reactivity occurs via activation of A2AAR.Support or Funding InformationLong Island University start‐up funding (DSP)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Apelin Increases Airway Responsiveness and Inflammation in a Mouse Model of Asthma

Apelin Increases Airway Responsiveness and Inflammation in a Mouse Model of Asthma

Swimming pool exposure is associated with autonomic changes and increased airway reactivity to a beta-2 agonist in school aged children: A cross-sectional survey.

BackgroundEndurance swimming exercises coupled to disinfection by-products exposure has been associated with increased airways dysfunction and neurogenic inflammation in elite swimmers. However, the impact of swimming pool exposure at a recreational level on autonomic activity has never been explored. Therefore, this study aimed to investigate how swimming pool attendance is influencing lung and autonomic function in school-aged children.MethodsA total of 858 children enrolled a cross sectional survey. Spirometry and airway reversibility to beta-2 agonist, skin-prick-tests and exhaled nitric oxide measurements were performed. Pupillometry was used to evaluate autonomic nervous function. Children were classified as current swimmers (CS), past swimmers (PS) and non-swimmers (NS), according to the amount of swimming practice.ResultsCurrent swimmers group had significantly lower maximum and average pupil constriction velocities when compared to both PS and NS groups (3.8 and 5.1 vs 3.9 and 5.3 vs 4.0 and 5.4 mm/s, p = 0.03 and p = 0.01, respectively). Moreover, affinity to the beta-2 agonist and levels of exhaled nitric oxide were significantly higher in CS when compared to NS (70 vs 60 mL and 12 vs 10 ppb, p<0.01 and p = 0.03, respectively). A non-significant trend for a higher risk of asthma, atopic eczema and allergic rhinitis was found with more years of swimming practice, particularly in atopic individuals (β = 1.12, 1.40 and 1.31, respectively). After case-case analysis, it was possible to observe that results were not influenced by the inclusion of individuals with asthma.ConclusionsConcluding, swimming pool attendance appears to be associated with autonomic changes and increased baseline airway smooth muscle constriction even in children without asthma.

Pulmonary IL-1β expression in early life causes permanent changes in lung structure and function in adulthood.

Chorioamnionitis, mechanical ventilation, oxygen therapy, and postnatal infection promote inflammation in the newborn lung. The long-term consequences of pulmonary inflammation during infancy have not been well characterized. The aim of this study was to examine the impact of inflammation during the late saccular to alveolar stages of lung development on lung structure and function in adulthood. To induce IL-1β expression in the pulmonary epithelium of mice with a tetracycline-inducible human IL-1β transgene, doxycycline was administered via intraperitoneal injections to bitransgenic pups and their littermate controls on postnatal days (PN) 0, 0.5, and 1. Lung structure, inflammation, and airway reactivity were studied in adulthood. IL-1β production in early life resulted in increased numbers of macrophages and neutrophils on PN21, but inflammation subsided by PN42. Permanent changes in alveolar structure, i.e., larger alveoli and thicker alveolar walls, were present from PN21 to PN84. Lack of alveolar septation thus persisted after IL-1β production and inflammation had ceased. Early IL-1β production caused goblet cell hyperplasia, enhanced calcium-activated chloride channel 3 (CLCA3) protein expression, and increased airway reactivity in response to methacholine on PN42. Lymphoid follicles were present adjacent to small airways in the lungs of adult bitransgenic mice, and levels of the B cell chemoattractant CXC-motif ligand (CXCL) 13 were elevated in the lungs of bitransgenic mice compared with controls. In conclusion, IL-1β-induced pulmonary inflammation in early life causes a chronic lung disease in adulthood.

Mer-mediated eosinophil efferocytosis regulates resolution of allergic airway inflammation

BackgroundEosinophils play a central role in propagation of allergic diseases, including asthma. Both recruitment and retention of eosinophils regulate pulmonary eosinophilia, but the question of whether alterations in apoptotic cell clearance by phagocytes contributes directly to resolution of allergic airway inflammation remains unexplored.ObjectivesIn this study we investigated the role of the receptor tyrosine kinase Mer in mediating apoptotic eosinophil clearance and allergic airway inflammation resolution in vivo to establish whether apoptotic cell clearance directly affects the resolution of allergic airway inflammation.MethodsAlveolar and bone marrow macrophages were used to study Mer-mediated phagocytosis of apoptotic eosinophils. Allergic airway inflammation resolution was modeled in mice by using ovalbumin. Fluorescently labeled apoptotic cells were administered intratracheally or eosinophil apoptosis was driven by administration of dexamethasone to determine apoptotic cell clearance in vivo.ResultsInhibition or absence of Mer impaired phagocytosis of apoptotic human and mouse eosinophils by macrophages. Mer-deficient mice showed delayed resolution of ovalbumin-induced allergic airway inflammation, together with increased airway responsiveness to aerosolized methacholine, increased bronchoalveolar lavage fluid protein levels, altered cytokine production, and an excess of uncleared dying eosinophils after dexamethasone treatment. Alveolar macrophage phagocytosis was significantly Mer dependent, with the absence of Mer attenuating apoptotic cell clearance in vivo to enhance inflammation in response to apoptotic cells.ConclusionsWe demonstrate that Mer-mediated apoptotic cell clearance by phagocytes contributes to resolution of allergic airway inflammation, suggesting that augmenting apoptotic cell clearance is a potential therapeutic strategy for treating allergic airway inflammation.

Airway reactivity to mannitol is similarly increased in chronic cigarette and water pipe smokers.

BackgroundIn contrast to cigarette smoking, the association between water pipe smoking and airway hyperresponsiveness remains widely unexplored.MethodsA bronchoprovocation challenge with mannitol was performed in young adults recruited at the University of Basel, Switzerland. Subjects were categorized as acute water pipe smokers (single episode of water pipe smoking, no or <0.5 pack-years cigarette smoking); chronic water pipe smokers (weekly for ≥4 weeks, no or <0.5 pack-years cigarette smoking); cigarette smokers (no water pipe smokers); and never-smokers (no cigarette or water pipe smokers). Primary outcomes were airway reactivity as measured by the response-to-dose ratio (RDR) and airway responsiveness measured by the provocation dose to cause a 15% fall in forced expiratory volume in 1s (FEV1; PD15).ResultsSeventy-four subjects with a mean age of 22.5±2.5 years and FEV1 % predicted 90.1%±8.6% were included. Subgroups were matched in terms of age, gender, and spirometry results. RDR in chronic water pipe smokers and cigarette smokers was similar (0.013%/mg [0.010–0.015] vs 0.023%/mg [0.011–0.051], respectively; p=0.12) but significantly higher than in never-smokers (0.007%/mg [0.005–0.010], p<0.01). Neither a history of asthma (p=0.88) nor a positive skin prick test (p=0.69) was associated with increased airway reactivity to the mannitol challenge test. PD15 differed significantly between cigarette smokers and never-smokers (155 mg [115–395] vs 315 mg [155–475], respectively; p=0.04).ConclusionWeekly water pipe smoking may increase airway reactivity to a similar extent as cigarette smoking.

Manipulation of dipeptidylpeptidase 10 in mouse and human in vivo and in vitro models indicates a protective role in asthma.

ABSTRACTWe previously identified dipeptidylpeptidase 10 (DPP10) on chromosome 2 as a human asthma susceptibility gene, through positional cloning. Initial association results were confirmed in many subsequent association studies but the functional role of DPP10 in asthma remains unclear. Using the MRC Harwell N-ethyl-N-nitrosourea (ENU) DNA archive, we identified a point mutation in Dpp10 that caused an amino acid change from valine to aspartic acid in the β-propeller region of the protein. Mice carrying this point mutation were recovered and a congenic line was established (Dpp10145D). Macroscopic examination and lung histology revealed no significant differences between wild-type and Dpp10145D/145D mice. However, after house dust mite (HDM) treatment, Dpp10 mutant mice showed significantly increased airway resistance in response to 100 mg/ml methacholine. Total serum IgE levels and bronchoalveolar lavage (BAL) eosinophil counts were significantly higher in homozygotes than in control mice after HDM treatment. DPP10 protein is present in airway epithelial cells and altered expression is observed in both tissue from asthmatic patients and in mice following HDM challenge. Moreover, knockdown of DPP10 in human airway epithelial cells results in altered cytokine responses. These results show that a Dpp10 point mutation leads to increased airway responsiveness following allergen challenge and provide biological evidence to support previous findings from human genetic studies. This article has an associated First Person interview with the first author of the paper.

SERUM MAGNESIUM LEVEL IN CHILDREN WITH BRONCHIAL ASTHMA IN DUHOK CITY

Background&#x0D; Asthma is an increasingly common disease over the last century. It is caused by chronic inflammation of lung airways with increased airway responsiveness and airflow obstruction. Magnesium is the fourth most common cation in the body and the major intracellular divalent cation. Mg+2 in extracellular fluid is crucial for normal neuromuscular activities. Magnesium deficiency is associated with increased contractility of smooth muscle cells including bronchiolar resulting in bronchospasm.&#x0D; Objectives&#x0D; To detect the prevalence of hypomagnesemia among asthmatic children and to find out any significant correlation of hypomagnesemia with asthma in children.&#x0D; Patients and Methods&#x0D; A case control study conducted in Duhok, North of Iraq in the period between January the 1st 2014 and January the 1st 2015. One hundred asthmatic patients aged between 1 and 15 years were examined. All patients had acute asthmatic attacks with features of respiratory distress for which they were admitted to Heevi Pediatric Teaching Hospital. Those with fever, dehydration, localized wheezing, pneumonia, cardiac, renal, or hepatic dysfunction were excluded. They were all studied in terms of age, gender, duration of asthma, drugs used for treatment, severity of asthma and the patients’ growth as measured by Body Mass index. Control group included 100 children who were healthy non asthmatic and visited the hospital with their parents. Samples of blood were taken to measure serum magnesium level.Statistical analysis were performed by using the SPSS 19 where P&lt;0.05 is significant.&#x0D; Results&#x0D; The mean serum magnesium in patients group was 1.91± 0.33 mg/dl while in the control group it was 2.03± 0.33 mg/dl. Serum magnesium levels were lower in the asthmatic patients than controls P= 0.01. Male gender predominated in both groups (68% , 61%) and the most common age among cases was 1- &lt; 3 years and controls 5- &lt;10 years. Serum magnesium level indirectly correlated with duration of asthma but not significantly (P=0.1). Serum magnesium level was not significantly related to body mass index P=0.3.Serum magnesium level decreased with increasing severity of asthma symptoms P= 0.05. Serum level is slightly lower in asthmatics on steroids and bronchodilators than those who were not P=0.7, P=0.9 respectively. &#x0D; Conclusion&#x0D; Serum magnesium level is significantly lower in asthmatic children as compared to the control group. Serum Mg+2 level decreases as the duration of asthma is longer but not significantly. There is an inverse relation between serum Mg+2 and the severity of asthma. No significant change in serum Mg+2 develops when steroids and bronchodilators are used.

Leukotriene receptor antagonist attenuated airway inflammation and hyperresponsiveness in a double-stranded RNA-induced asthma exacerbation model

BackgroundViral infections are the most common triggers of asthma exacerbation, but the key molecules involved in this process have not been fully identified. Although cysteinyl leukotrienes (cysLTs) have been postulated as the key mediators, their precise roles remain largely unclear. To investigate the roles of cysLTs in virus-induced asthma exacerbation, we developed a murine model using a viral double-stranded RNA analog, polyinosinic–polycytidylic acid (poly I:C), and analyzed the effect of leukotriene receptor antagonist (LTRA) administration. MethodsA/J mice were immunized with ovalbumin (OVA) + alum (days 0, 28, 42, and 49), followed by intranasal challenge with OVA (phase 1: days 50–52) and poly I:C (phase 2: days 53–55). Montelukast was administered during poly I:C challenge (phase 2) in the reliever model or throughout the OVA and poly I:C challenges (phases 1 and 2) in the controller model. Airway responsiveness to acetylcholine chloride was assessed, and bronchoalveolar lavage (BAL) was performed on day 56. ResultsAdministration of poly I:C to OVA-sensitized and -challenged mice increased the number of eosinophils and levels of IL-13, IL-9, CCL3, and CXCL1 in BAL fluid (BALF) and tended to increase airway responsiveness. Montelukast significantly attenuated the poly I:C-induced increase in the number of eosinophils and levels of IL-13, IL-9, and CCL3 in BALF and airway hyperresponsiveness in both the reliever and controller models. ConclusionsThis is the first report showing that LTRA functionally suppressed the pathophysiology of a virus-induced asthma exacerbation model, suggesting the importance of cysLTs as a potential treatment target.

Cigarette Smoke Increases CD8α+ Dendritic Cells in an Ovalbumin-Induced Airway Inflammation.

Asthma is an allergic lung disease and, when associated to cigarette smoke exposition, some patients show controversial signs about lung function and other inflammatory mediators. Epidemiologic and experimental studies have shown both increasing and decreasing inflammation in lungs of subjects with asthma and exposed to cigarette smoke. Therefore, in this study, we analyzed how cigarette smoke affects pro-inflammatory and anti-inflammatory mediators in a murine model of allergic pulmonary inflammation. We sensitized Balb/c mice to ovalbumin (OVA) with two intraperitoneal injections. After sensitization, the animals were exposed to cigarette smoke twice a day, 30 min per exposition, for 12 consecutive days. In order to drive the cell to the lungs, four aerosol challenges were performed every 48 h with the same allergen of sensitization. OVA sensitization and challenge developed pulmonary Th2 characteristic response with increased airway responsiveness, remodeling, increased levels of IgE, interleukin (IL)-4, and IL-13. Cigarette smoke, unexpectedly, reduced the levels of IL-4 and IL-13 and simultaneously decreased anti-inflammatory cytokines as IL-10 and transforming growth factor (TGF)-β in sensitized and challenged animals. OVA combined with cigarette smoke exposition decreased the number of eosinophils in bronchoalveolar lavage and increased the number of neutrophils in lung. The combination of cigarette smoke and lung allergy increased recruitment of lymphoid dendritic cells (DCs) into lymph nodes, which may be the leading cause to an increase in number and activation of CD8+ T cells in lungs. In addition, lung allergy and cigarette smoke exposure decreased an important regulatory subtype of DC such as plasmacytoid DC as well as its activation by expression of CD86, PDL2, and ICOSL, and it was sufficient to decrease T regs influx and anti-inflammatory cytokines release such as IL-10 and TGF-β but not enough to diminish the structural changes. In conclusion, we observed, in this model, that OVA sensitization and challenge combined with cigarette smoke exposure leads to mischaracterization of the Th2 response of asthma by decreasing the number of eosinophils, IL-4, and IL-13 and increasing number of neutrophils, which is related to the increased number of CD8ɑ+ DCs and CD8+ T cells as well as reduction of the regulatory cells and its released cytokines.

Benzalkonium Chloride: A Bronchoconstricting Preservative in Continuous Albuterol Nebulizer Solutions.

For convenience, many pediatric hospitals are preparing solutions for continuous nebulized albuterol using the 0.5% 20-ml multidose albuterol dropper bottle. This product contains benzalkonium chloride (BAC) that, by itself, produces bronchospasm that is dose dependent and cumulative. The bronchoconstrictive effects of BAC are greater in patients with more severe airway obstruction and increased airway responsiveness. Use of BAC-containing albuterol during severe acute asthma exacerbations may antagonize the bronchodilator response to albuterol, prolong treatment, and increase the risk of albuterol-related systemic adverse effects. Such a deleterious effect of BAC is difficult to detect because some patients improve slowly or may even worsen during treatment. We recommend that only preservative-free albuterol products be used.

The Effect of in vivo High Molecular Weight Hyaluronan Treatment on Airway Reactivity in a Neonatal Mouse Model of Continuous Positive Airway Pressure (CPAP)

Although continuous positive airway pressure (CPAP) is a commonly used mode of respiratory support in the care of pre‐term infants, its long‐term effects on lung development and airway reactivity are largely unknown. Previously, we developed a neonatal mouse model of CPAP and showed that it caused a long‐term increase in airway reactivity to methacholine challenge. In the current study we tested the hypotheses that hyaluronan (HA), a major component of lung extracellular matrix, plays a role in the airway hyper‐reactivity (AHR) following neonatal CPAP and whether it can be prevented by exogenous administration of high molecular weight HA. Neonatal mice received CPAP (6cm H2O) for 3 hours per day for the first 7 postnatal days. Control animals experienced the same conditions as experimental animals only with no CPAP. On days 3 and 7, a subset of mice in each group received sub‐cutaneous injections of 1% high molecular weight HA (&gt;1000kD, 20μl/g). Two weeks after CPAP ended (postnatal (P) age 21 days), mice were sacrificed and lungs prepared for measurements of airway reactivity to increasing doses of methacholine (0.25μM‐8μM) using the precision cut lung slice method. Airway reactivity to methacholine was increased in P21 mice that received CPAP during the first postnatal week compared to untreated control mice. Gel electrophoresis analysis of whole lung homogenates revealed CPAP also increased total lung HA levels. Immunohistochemical staining of HA with an antibody selective for the hyaluronan binding protein (HABP) showed increased HA expression around the airways within or in the vicinity of airway smooth muscle. However, mice that also received high molecular weight HA during CPAP displayed decreased reactivity to methacholine challenge when compared to airways from animals that received CPAP alone. High molecular weight HA administration also prevented the increased total HA expression caused by CPAP. We conclude that lung HA plays a role in the long‐term increase in AHR following neonatal CPAP, although exogenous administration of high molecular weight HA appears to be protective against such adverse effects of CPAP. These data may have important implications for the way CPAP may contribute to the pathophysiology of wheezing disorders commonly seen in preterm infants.Support or Funding InformationNHLBI PO1HL107147

Apelin Increases Airway Reactivity and Inflammation in a Mouse Model of Asthma

There is evidence that inflammatory exacerbations in asthma may be mediated by specific endogenous peptides. Apelin, an endogenous hypotensive and angiogenic peptide, is increased in atopic asthma. However, it is unclear how apelin affects allergic inflammation observed in asthma. We studied the role of exogenously administered apelin in airway hyperreactivity and inflammation in allergic mice. Mice were divided into control (CON) and allergen sensitized‐challenged (SEN) groups. Mice were sensitized (i.p.) on days 1, 6 with 0.2μg ovalbumin (OVA) followed by 5% OVA aerosol challenges on days 11–13. Apelin was given i.p. as a single bolus dose (4mg/kg) on day 14 to SEN mice. Whole body plethysmography (measuring airway responsiveness as enhanced pause, Penh) and bronchoalveolar lavage (BAL) studies were then performed. Airway responsiveness to MCh (48mg/ml) was highest in SEN+APELIN group (149.64±6116 vs. 95.16±30.48% in SEN, p&gt;0.05, n=3). Differential BAL cell analysis showed that treatment with apelin increased eosinophils (68.67±1.86% in SEN vs 80.67 ±1.20% in SEN+APELIN, p&lt;0.05) and neutrophils (8.33±0.88% in SEN vs 13.33±0.88% in SEN+APELIN, p&lt;0.05) in sensitized mice, thus potentiating the allergic inflammation. Although further studies are needed to evaluate detailed cellular mechanisms, the role of apelin and apelinergic system appears to be proinflammatory in this model of asthma.Support or Funding InformationLIU start‐up funds (DSP)

Effects of Lignocaine Administered Intravenously or Intratracheally on Airway and Hemodynamic Responses during Emergence and Extubation in Patients Undergoing Elective Craniotomies in Supine Position.

Introduction:Sympathoadrenergic responses during emergence and extubation can lead to an increase in heart rate (HR) and blood pressure whereas increased airway responses may lead to coughing and laryngospasm. The aim of our study was to compare the effects of lignocaine administered intravenously (IV) or intratracheally on airway and hemodynamic responses during emergence and extubation in patients undergoing elective craniotomies.Methodology:Sixty patients with physical status American Society of Anaesthesiologists Classes I and II aged 18–70 years, scheduled to undergo elective craniotomies were included. The patients were randomly divided into three groups of twenty patients; Group 1 receiving IV lignocaine and intratracheal placebo (IV group), Group 2 receiving intratracheal lignocaine and IV placebo (I/T group), and Group 3 receiving IV and intratracheal placebo (placebo group). The tolerance to the endotracheal tube was monitored, and number of episodes of cough was recorded during emergence and at the time of extubation. Hemodynamic parameters such as HR and blood pressure (systolic, diastolic, mean arterial pressure) were also recorded.Results:There was a decrease of HR in both IV and intratracheal groups in comparison with placebo group (P < 0.005). Rise in blood pressure (systolic blood pressure, diastolic blood pressure and mean arterial pressure) was comparable in both Groups 1 and 2 but was lower in comparison with placebo group (P < 0.005). Cough suppression was comparable in all the three groups. Grade III cough (15%) was documented only in placebo group.Conclusion:Both IV and intratracheal lignocaine are effective in attenuation of hemodynamic response if given within 20 min from skull pin removal to extubation. There was comparable cough suppression through intratracheal route and IV routes than the placebo group.

Chromosome 17q21 Genes ORMDL3 and GSDMB in Asthma and Immune Diseases.

Chromosome 17q21 contains a cluster of genes including ORMDL3 and GSDMB, which have been highly linked to asthma in genome-wide association studies. ORMDL3 is localized to the endoplasmic reticulum and regulates downstream pathways including sphingolipids, metalloproteases, remodeling genes, and chemokines. ORMDL3 inhibits serine palmitoyl-CoA transferase, the rate-limiting enzyme for sphingolipid biosynthesis. In addition, ORMDL3 activates the ATF6α branch of the unfolded protein response which regulates SERCA2b and IL-6, pathways of potential importance to asthma. The SNP-linking chromosome 17q21 to asthma is associated with increased ORMDL3 and GSDMB expression. Mice expressing either increased levels of human ORMDL3, or human GSDMB, have an asthma phenotype characterized by increased airway responsiveness and increased airway remodeling (increased smooth muscle and fibrosis) in the absence of airway inflammation. GSDMB regulates expression of 5-LO and TGF-β1 which are known pathways involved in the pathogenesis of asthma. GSDMB is one of four members of the GSDM family (GSDMA, GSDMB, GSDMC, and GSDMD). GSDMD (located on chromosome 8q24 and not linked to asthma) has emerged as a key mediator of pyroptosis. GSDMD is a key component of the NLPR3 inflammasome and is required for its activation. GSDMD undergoes proteolytic cleavage by caspase-1 to release its N-terminal fragment, which in turn mediates pyroptosis and IL-1β secretion. Chromosome 17q21 has not only been linked to asthma but also to type 1 diabetes, inflammatory bowel disease, and primary biliary cirrhosis suggesting that future insights into the biology of genes located in this region will increase our understanding of these diseases.

The relationship between body mass index and increased airway reactivity based on methacholine challenge test results.

IntroductionAccording to the reports of the United States National Bureau of Statistics regarding the prevalence of obesity among adults and children and also asthma outbreak, the relationship between asthma and obesity in developed countries is taken into consideration.AimRelationship between body mass index and increased airway reactivity based on methacholine challenge test results.Material and methodsIt was a retrospective cross-sectional study done on 256 patients who were referred to the lung clinic of the Imam Khomeini Hospital of Ahvaz with symptoms of hypersensitivity of the airways. The patients, who had normal spirometry, were examined by the methacholine challenge test and then they were divided in two groups with positive and negative test results.ResultsThe patients of this study were 12–84 years old and their average age was 36.3 ±12.1 years. Their mean body mass index (BMI) was 28 ±4.7 kg/m2 in the group with positive methacholine and 26.7 ±4.9 kg/m2 in the group with negative methacholine (p = 0.04). It was shown that there has been a statistically significant relationship between BMI and positive methacholine challenge test results (apart from confounding effects of other variables). It seems that the positivity rate of methacholine test rises by 1.06 with an increase in BMI by each unit (p < 0.05).ConclusionsAccording to the results of this study, it can be said that in high BMI there is a statistically significant association between gender (female) and a positive methacholine challenge test result; but there is no statistically significant association between the methacholine dose and BMI.