Airway Responsiveness Research Articles

Evaluation of barometric whole-body plethysmography for therapy monitoring in cats with feline lower airway disease.

ObjectivesFeline lower airway disease (FLAD) is a common respiratory condition in cats. Traditionally, response to therapy is monitored only by evaluation of clinical signs and radiographic examination of the lungs. Barometric whole-body plethysmography (BWBP) is considered a non-invasive, well-tolerated form of measuring airway reactivity in cats. The aim of the study was to assess pulmonary function testing by BWBP for non-invasive evaluation of response to therapy in cats with FLAD and to investigate whether BWBP parameters correlate with clinical severity.Material and methodsThe prospective study included 25 client-owned cats, diagnosed with FLAD on the basis of their medical history, clinical signs, radiographic findings, and bronchoalveolar lavage fluid (BALF) examination. At three time points (day 0, 14, and 60), a standardised owner questionnaire, a clinical examination and BWBP measurements were carried out. Results of the questionnaire and the clinical examination were evaluated using a clinical 12-point score. Individual therapy was administered to all patients after diagnosis, based on the severity of disease and compliance of the cat.ResultsThe total clinical score significantly improved over the entire study period (p<0.001). Significant improvement was detected for the frequency of coughing (p = 0.009), respiratory distress (p = 0.001), lung auscultation findings (p = 0.002), and general condition and appetite (p = 0.045). The BWBP parameter Penh, an indicator of bronchoconstriction, improved significantly under initial therapy between day 0 and 14 (p = 0.009). A significant correlation between Penh and the severity of auscultation findings was seen on day 0 (r = 0.40; p = 0.013).ConclusionThe study supports the role of Penh as a non-invasive parameter for monitoring initial treatment response in cats with FLAD. Further studies are needed to address whether other BWBP parameters might be suitable for non-invasive therapy monitoring of FLAD. Clinical evaluation is always essential in cats with FLAD to evaluate treatment response.

Design and Implementation of Airway Response Teams to Improve the Practice of Emergency Airway Management.

Emergency airway management (EAM) is a commonly performed procedure in the critical care setting. Despite clinical advances that help practitioners identify patients at risk for having a difficult airway, improved airway management tools, and algorithms that guide clinical decision-making, the practice of EAM is associated with significant morbidity and mortality. Evidence suggests that a dedicated airway response team (ART) can help mitigate the risks associated with EAM and provide a framework for airway management in acute settings. We review the risks and challenges related to EAM and describe strategies to improve patient care and outcomes via implementation of an ART.

Efficiency of using a short-acting β2-agonist for the relief of acute cold bronchospasm in asthma patients with cold airway hyperresponsiveness

Excessive sensitivity of the respiratory tract to physical and chemical environmental triggers can vary for many reasons, reducing the therapy effectiveness in a patient with asthma. Aim of the study was to investigate the effectiveness of a short-acting bronchodilator in patients with asthma for the relief of acute cold bronchospasm after a test of isocapnic cold air hyperventilation (ICHV). Material and methods. In 281 (161 women; 120 men, p &gt; 0.05) asthma patients with cold airway hyperresponsiveness (CAHR), the change in airway patency (FEV1) and the efficacy of short-acting β2-agonists (SABA) after a 3-minute isocapnic hyperventilation with cold (–20 ºС) air. Results. According to clinical data, patients had persistent asthma, mean age 35 (26; 44) years, 49 % of patients smoked, ACT 16 (12; 20) points, FEV1 90.0 ± 1.0 % predicted, FEV1/VC 71.4 ± 0.6 %, the increase in FEV1 after inhalation of SABA (∆FEV1β) was 11.1 (5.1; 20.5) %. The change in FEV1 for the ICHV varied within –16 (–22.0; –12.0) %. The use of SABA after the IHCV showed different efficacy for relief of an attack of cold bronchospasm. The median value of ∆FEV1β after ICHV was 21.1 (11.6; 33.3) %, with a range of –48.6 to 108.2 %. In the general group, there was a direct relationship between the level of asthma control in terms of ACT points and the baseline FEV1 (Rs = 0.17; p = 0.007), MEF25-75 (Rs = 0.18; p = 0.008), ∆FEV1β in response to SABA (Rs = –0.17; p = 0.0104), as well as the severity of the bronchial response to the ICHV (Rs = 0.15; p = 0.014). The latter, in turn, correlated with ∆FEV1β after ICHV (Rs = –0.28; p &lt; 0.0001) after HCI. Conclusions. There is a differentiated airway response to SABA after acute cold bronchoprovocation. The results obtained can serve as an important tool for phenotyping of asthma patients with CAHR for the medication correction of сold bronchospasm.

Interleukin-11 receptor subunit α-1 is required for maximal airway responsiveness to methacholine after acute exposure to ozone.

Interleukin (IL)-11, a multifunctional cytokine, contributes to numerous biological processes, including adipogenesis, hematopoiesis, and inflammation. Asthma, a respiratory disease, is notably characterized by reversible airway obstruction, persistent lung inflammation, and airway hyperresponsiveness (AHR). Nasal insufflation of IL-11 causes AHR in wild-type mice while lung inflammation induced by antigen sensitization and challenge, which mimics features of atopic asthma in humans, is attenuated in mice genetically deficient in IL-11 receptor subunit α-1 (IL-11Rα1-deficient mice), a transmembrane receptor that is required conjointly with glycoprotein 130 to transduce IL-11 signaling. Nevertheless, the contribution of IL-11Rα1 to characteristics of nonatopic asthma is unknown. Thus, based on the aforementioned observations, we hypothesized that genetic deficiency of IL-11Rα1 attenuates lung inflammation and increases airway responsiveness after acute inhalation exposure to ozone (O3), a criteria pollutant and nonatopic asthma stimulus. Accordingly, 4 and/or 24 h after cessation of exposure to filtered room air or O3, we assessed lung inflammation and airway responsiveness in wild-type and IL-11Rα1-deficient mice. With the exception of bronchoalveolar lavage macrophages and adiponectin, which were significantly increased and decreased, respectively, in O3-exposed IL-11Rα1-deficient as compared with O3-exposed wild-type mice, no other genotype-related differences in lung inflammation indices that we quantified were observed in O3-exposed mice. However, airway responsiveness to acetyl-β-methylcholine chloride (methacholine) was significantly diminished in IL-11Rα1-deficient as compared with wild-type mice after O3 exposure. In conclusion, these results demonstrate that IL-11Rα1 minimally contributes to lung inflammation but is required for maximal airway responsiveness to methacholine in a mouse model of nonatopic asthma.

Mild allergic airways responses to an environmental mixture increase cardiovascular risk in rats.

Recent epidemiological findings link asthma to adverse cardiovascular responses. Yet, the precise cardiovascular impacts of asthma have been challenging to disentangle from the potential cardiovascular effects caused by asthma medication. The purpose of this study was to determine the impacts of allergic airways disease alone on cardiovascular function in an experimental model. Female Wistar rats were intranasally sensitized and then challenged once per week for 5 weeks with saline vehicle or a mixture of environmental allergens (ragweed, house dust mite, and Aspergillus fumigatus). Ventilatory and cardiovascular function, measured using double-chamber plethysmography and implantable blood pressure (BP) telemetry and cardiovascular ultrasound, respectively, were assessed before sensitization and after single and final allergen challenge. Responses to a single 0.5 ppm ozone exposure and to the cardiac arrhythmogenic agent aconitine were also assessed after final challenge. A single allergen challenge in sensitized rats increased tidal volume and specific airways resistance in response to provocation with methacholine and increased bronchoalveolar lavage fluid (BALF) eosinophils, neutrophils, lymphocytes, cytokines interleukin (IL)-4, IL-5, IL-10, IL-1β, tumor necrosis factor-α, and keratinocyte chemoattract-growth-related oncogene characteristic of allergic airways responses. Lung responses after final allergen challenge in sensitized rats were diminished, although ozone exposure increased BALF IL-6, IL-13, IL-1 β, and interferon-γ and modified ventilatory responses only in the allergen group. Final allergen challenge also increased systolic and mean arterial BP, stroke volume, cardiac output, end-diastolic volume, sensitivity to aconitine-induced cardiac arrhythmia, and cardiac gene expression with lesser effects after a single challenge. These findings demonstrate that allergic airways responses may increase cardiovascular risk in part by altering BP and myocardial function and by causing cardiac electrical instability.

This Month in Anesthesiology

This Month in Anesthesiology

Anti-asthmatic miR-224-5p inhibits the FHL1/MAPK pathway to repress airway smooth muscle cell proliferation in a murine model of asthma-like airway inflammation

BackgroundThe proliferation of airway smooth muscle cells (ASMCs) contributes to the contractility and inflammation in the pathophysiology of asthma. This intrigued us to clarify the effect of microRNA (miR)-224-5p on biological characteristics of ASMCs in mice with asthma-like airway inflammation and responses through the FHL1-dependent MAPK pathway.MethodsAn ovalbumin (OVA)-induced asthma mouse model was established, where ASMCs were isolated. The expression of FHL1 was determined in asthmatic mice. Artificial modulation of FHL1 expression was performed to explore its effect on airway inflammation of asthmatic mice and ASMC proliferation and apoptosis. Afterwards, we analyzed the interaction among miR-224-5p, FHL1 and the MAPK pathway, and explored their combined impacts on airway inflammation of asthmatic mice and ASMC proliferation and apoptosis.ResultsFHL1 was highly expressed and miR-224-5p was poorly expressed in asthmatic mice. FHL1 was verified to be a target of miR-224-5p. Loss of FHL1 function reduced airway inflammation in asthmatic mice and proliferation of ASMCs while inducing their apoptosis. Besides, miR-224-5p inhibited the MAPK pathway by binding to FHL1. Overexpression of miR-224-5p relieved airway inflammation, inhibited ASMC proliferation, and increased apoptosis, which could be reversed by overexpression of FHL1.ConclusionAltogether, miR-224-5p inhibited airway inflammation in asthmatic mice and ASMC proliferation through blocking the MAPK pathway by down-regulating FHL1.

I-GEL versus LMA classic: Comparison of two supraglottic airway devices in short surgical procedures

Background: Supraglottic airway devices are more efficient than endotracheal intubation in management of difficult airway and hemodynamic response. Aims and Objectives: This study was undertaken for to compare laryngeal mask airway (LMA) Classic and I-Gel in terms of ease of insertion, insertion attempts, time taken for insertion, hemodynamic change, and adverse events after administering muscle relaxants for airway management in short surgical procedures. Materials and Methods: A total of 120 patients of American Society of Anaesthesiologist 1 and II, aged between 18 and 50 years with Malampatti score 1 and II posted for elective short surgical cases were randomly allotted into two groups (n=60 in each), Group A for LMA Classic and Group B for I-gel. Patients were pre oxygenated with 100% O2 and pre-medicated. After induction and proper muscle relaxation, LMA Classic or I-GEL was inserted. The time and number of insertion attempts were assessed. Heart rate, Blood pressure, SpO2 recorded at the time of insertion, 1, 3, 5, and 10 min following insertion. The recorded results were analyzed statistically. Results: The mean insertion time of Group A was 34.80±3.193 and Group B was 21.72±1.975. P&lt;0.001 and in Group B all patients were successfully intubated at first attempt whereas in Group B 23.33% patients required second attempts. Hemodynamic changes were also less with Group B. Conclusion: I-Gel has better hemodynamic stability. Ease of Insertion, insertion attempts and time taken for insertion are more convenient for I-Gel than LMA Classic after administering muscle relaxants.

A CASE OF MYCOBACTERIUM AVIUM COMPLEX PULMONARY INFECTION WITH SEVERE EOSINOPHILIA TREATED WITH MEPOLIZUMAB

A CASE OF MYCOBACTERIUM AVIUM COMPLEX PULMONARY INFECTION WITH SEVERE EOSINOPHILIA TREATED WITH MEPOLIZUMAB

Th1, Th2 cytokines in airway response to acute cold exposure in patients with bronchial asthma

Introduction. The concept of the interaction of multidirectional cytokines that control the cellular and humoral immune response in the cold bronchospasm in asthma has been little studied.Aim. To evaluate the role of Th1 and Th2 cytokines in the formation of the airway response to a cold stimulus in patients with asthma.Materials and methods. The spectrum of cytokines (IFN-γ, IL-17А, TNFα, IL-1β, IL-2, IL-6, IL-4), protein IP-10 (chemokine CXCL10), MMP9 metalloproteinase and TIMP1 protein in exhaled breath condensate before and after 3-minute isocapnic hyperventilation with cold (-20ºС) air (IHCA) has been studied in 37 patients.Results. Patients were divided into two groups: group 1 (n=11) consisted of individuals with cold airway hyperresponsiveness (CAHR), group 2 – 26 individuals with no response to IHCA (ΔFEV1 IHCA = -16.5±2.3 and -1.5±0.85%, respectively, p&lt;0.0001). Pro-inflammatory cytokines TNFα, IL-2, IL-1β, and IL-6 had a predominant effect on the development of CAHR. IFN-γ was considered as a central regulator of the bronchial response to a cold stimulus, the increase in the level of which in cold bronchospasm relative to the group without CAHR (399,52 [237,1; 753,23] and 237,99 [57,63; 304,84] fg/mL, respectively, p&lt;0.05) was accompanied by an increase in the concentration of IFN-γ-induced protein IP-10 (201.12 [199.4; 398.81] and 167.33 [132.94; 212.77] fg/mL, respectively (p&lt;0.05). The absence of dynamics of IL-4 concentration in response to IHCA testified to the minimal involvement of IL-4 in the implementation of CAHR. The involvement of IL-17A could be associated with the activity of Th1 cytokines and the cold-activated proteolysis-antiproteolysis system involved in bronchial remodeling ‒ metalloproteinase MMP9 and a specific inhibitor of metalloproteinases TIMP1, the values of the latter two were higher in individuals with CAHR after the IHCA test.Conclusion. In patients with asthma, in the implementation of cold bronchospasm, the dominance of the Th1 immune response and a decrease in the functional activity of Th2 cytokines are observed.

The Effectiveness and Safety of Huangqi Xixin Decoction for Cough Variant Asthma: A Systematic Review and Meta-Analysis.

Objective A comprehensive and systematic review is needed to evaluate the safety and effectiveness of Huangqi Xixin decoction (HQXXD) for cough variant asthma (CVA). In this systematic review, we comprehensively interrogate the safety and effectiveness of HQXXD for CVA. Methods An overall search for studies in main English and Chinese electronic databases from their inception to June 30, 2022, was performed. Randomized controlled trials (RCTs) involving HQXXD for CVA were included. According to Cochrane Reviewer's Handbook, the risk of bias related to the included studies was evaluated. A meta-analysis using RevMan 5.4 software from the Cochrane Collaboration was used to integrate the outcomes of the included RCTs. Results A systematic review and meta-analysis were conducted using the seven eligible RCTs that had been retrieved. The included RCT-related risk of bias was evaluated. According to the findings of the meta-analysis, the HQXXD group had significantly higher total effective rates of clinical efficacy and airway responsiveness, and a significantly lower recurrence rate in comparison with the conventional Western medicine treatment group. Conclusion In the treatment of CVA patients, HQXXD is safe and effective, which benefits clinical efficacy and airway responsiveness, reduces the recurrence rate, and has no adverse effects.

The Nicotinic Receptor Polymorphism rs16969968 Is Associated with Airway Remodeling and Inflammatory Dysregulation in COPD Patients.

Genome-wide association studies unveiled the associations between the single nucleotide polymorphism rs16969968 of CHRNA5, encoding the nicotinic acetylcholine receptor alpha5 subunit (α5SNP), and nicotine addiction, cancer, and COPD independently. Here, we investigated α5SNP-induced epithelial remodeling and inflammatory response in human COPD airways. We included 26 α5SNP COPD patients and 18 wild-type α5 COPD patients in a multi-modal study. A comparative histologic analysis was performed on formalin-fixed paraffin-embedded lung tissues. Isolated airway epithelial cells from bronchial brushings were cultivated in the air-liquid interface. Broncho-alveolar fluids were collected to detect inflammatory mediators. Ciliogenesis was altered in α5SNP COPD bronchial and bronchiolar epithelia. Goblet cell hyperplasia was exacerbated in α5SNP small airways. The broncho-alveolar fluids of α5SNP COPD patients exhibited an increase in inflammatory mediators. The involvement of the rs16969968 polymorphism in airway epithelial remodeling and related inflammatory response in COPD prompts the development of innovative personalized diagnostic and therapeutic strategies.

Clinical effects and pharmacokinetics of nebulized lidocaine in healthy horses.

BackgroundNebulized lidocaine appears promising as a novel corticosteroid-sparing therapeutic for equine asthma, but its safety and pharmacokinetic behavior have yet to be confirmed.ObjectiveTo describe the effect of nebulized lidocaine on upper airway sensitivity, lung mechanics, and lower respiratory cellular response of healthy horses, as well as delivery of lidocaine to lower airways, and its subsequent absorption, clearance, and duration of detectability.AnimalsSix healthy university- and client-owned horses with normal physical examination and serum amyloid A, and no history of respiratory disease within 6 months.MethodsProspective, descriptive study evaluating the immediate effects of 1 mg/kg 4% preservative-free lidocaine following nebulization with the Flexineb®. Prior to and following nebulization, horses were assessed using upper airway endoscopy, bronchoalveolar lavage, and pulmonary function testing with esophageal balloon/pneumotachography and histamine bronchoprovocation. Additionally, blood and urine were collected at predetermined times following single-dose intravenous and nebulized lidocaine administration for pharmacokinetic analysis.ResultsUpper airway sensitivity was unchanged following lidocaine nebulization, and no laryngospasm or excessive salivation was noted. Lidocaine nebulization (1 mg/kg) resulted in a mean epithelial lining fluid concentration of 9.63 ± 5.05 μg/mL, and a bioavailability of 29.7 ± 7.76%. Lidocaine concentrations were higher in epithelial lining fluid than in systemic circulation (Cmax 149.23 ± 78.74 μg/L, CELF:Cmaxplasma 64.4, range 26.5–136.8). Serum and urine lidocaine levels remained detectable for 24 and 48 h, respectively, following nebulization of a single dose. Baseline spirometry, lung resistance and dynamic compliance, remained normal following lidocaine nebulization, with resistance decreasing post-nebulization. Compared to the pre-nebulization group, two additional horses were hyperresponsive following lidocaine nebulization. There was a significant increase in mean airway responsiveness post-lidocaine nebulization, based on lung resistance, but not dynamic compliance. One horse had BAL cytology consistent with airway inflammation both before and after lidocaine treatment.ConclusionsNebulized lidocaine was not associated with adverse effects on upper airway sensitivity or BAL cytology. While baseline lung resistance was unchanged, increased airway reactivity to histamine bronchoprovocation in the absence of clinical signs was seen in some horses following nebulization. Further research is necessary to evaluate drug delivery, adverse events, and efficacy in asthmatic horses.

Obesity in women with asthma: Baseline disadvantage plus greater small-airway responsiveness.

Obesity is known to diminish lung volumes and worsen asthma. However, mechanistic understanding is lacking, especially as concerns small-airway responsiveness. The objective of this study was therefore to compare small-airway responsiveness, as represented by the change in expiratory:inspiratory mean lung density ratios (MLDe/i , as determined by computed tomography [CT]) throughout methacholine testing in obese versus non-obese women with asthma. Thoracic CT was performed during methacholine bronchoconstriction challenges to produce standardized response curves (SRC: response parameter versus ln[1 + % PD20], where PD20 is the cumulative methacholine dose) for 31 asthma patients (n=18 non-obese and n=13 obese patients). Mixed models evaluated obesity effects and interactions on SRCs while adjusting for age and bronchial morphology. Small airway responsiveness as represented by SRC slope was calculated for each third of the MLDe/i response and compared between groups. Obesity-associated effects observed during experimental bronchoconstriction included: (i) a significant baseline effect for forced expiratory volume in 1 second with lower values for the obese (73.11 ± 13.44) versus non-obese (82.19 ± 8.78; p=0.002) groups prior to methacholine testing and (ii) significantly higher responsiveness in small airways as estimated via differences in MLDe/i slopes (group×ln(1 + % PD20 interaction; p=0.023). The latter were pinpointed to higher slopes in the obese group at the beginning 2/3 of SRCs (p=0.004 and p=0.021). Significant obesity effects (p=0.035 and p=0.008) indicating lower forced vital capacity and greater % change in MLDe/I (respectively) throughout methacholine testing, were also observed. In addition to baseline differences, small-airway responsiveness (as represented by the change in MLDe/i ) during methacholine challenge is greater in obese women with asthma as compared to the non-obese.

Protection against SARS-CoV-2 transmission by a parenteral prime-Intranasal boost vaccine strategy.

BackgroundLicensed vaccines against SARS-CoV-2 effectively protect against severe disease, but display incomplete protection against virus transmission. Mucosal vaccines providing immune responses in the upper airways are one strategy to protect against transmission.MethodsWe administered Spike HexaPro trimer formulated in a cationic liposomal adjuvant as a parenteral (subcutaneous – s.c.) prime - intranasal boost regimen to elicit airway mucosal immune responses and evaluated this in a Syrian hamster model of virus transmission.FindingsParenteral prime - intranasal boost elicited high-magnitude serum neutralizing antibody responses and IgA responses in the upper respiratory tract. The vaccine strategy protected against virus in the lower airways and lung pathology, but virus could still be detected in the upper airways. Despite this, the parenteral prime - intranasal booster vaccine effectively protected against onward SARS-CoV-2 transmission.InterpretationThis study suggests that parenteral-prime mucosal boost is an effective strategy for protecting against SARS-CoV-2 infection and highlights that protection against virus transmission may be obtained despite incomplete clearance of virus from the upper respiratory tract. It should be noted that protection against onward transmission was not compared to standard parenteral prime-boost, which should be a focus for future studies.FundingThis work was primarily supported by the European Union Horizon 2020 research and innovation program under grant agreement no. 101003653.

Relationship between Serum IgE and Airway Responsiveness in Adults with Asthma

Relationship between Serum IgE and Airway Responsiveness in Adults with Asthma

Airway autoimmunity, asthma exacerbations, and response to biologics.

Biologic therapies in asthma are indicated in severe disease, and they are directed against specific inflammatory modulators that contribute to pathogenesis and severity. Currently approved biologics target T2 cytokines (IgE, IL-5, IL-4/IL-13, and TLSP) and have demonstrated efficacy in clinical outcomes such as exacerbation rate and oral corticosteroid dose reductions, blood and airway eosinophil depletion, and lung function improvement. However, a proportion of these patients may show inadequate responses to biologics, with either initial lack of improvement or clinical and functional worsening after an optimal initial response. Exacerbations while on a biologic may be due to several reasons, including imprecise identification of the dominant effector pathway contributing to severity, additional inflammatory pathways that are not targeted by the biologic, inaccuracies of the biomarker used to guide therapy, inadequate dosing schedules, intercurrent airway infections, anti-drug neutralizing antibodies, and a novel phenomenon of autoimmune responses in the airways interfering with the effectiveness of the monoclonal antibodies. This review, illustrated using case scenarios, describes the underpinnings of airway autoimmune responses in driving exacerbations while patients are being treated with biologics, device a strategy to evaluate such exacerbations, an algorithm to switch between biologics, and perhaps to consider two biologics concurrently.

Mycobacterium Vaccae Regulate γδT17 and γδTreg Cells in Mice Asthmatic Lung.

Background Dysregulation of the balance between different T cell populations is believed to be an important basis for asthma.Objective To observe the changes in γδT subtypes in transgenic asthmatic mice after aerosol inhalation of Mycobacterium vaccae, and to further investigate the mechanism of M. vaccae in asthmatic mice and its relationship with γδT cells.Methods TCR-β-/- mice were exposed to atomized normal saline or M. vaccae for 5 days and the γδT cells from the lung tissues were isolated. Changes in γδT17 and γδTreg populations were detected. Asthma was induced in BALB/c mice using ovalbumin, which was then transplanted with control or M. vaccae-primed γδT cells. First we analyzed the content of γδT cells that secrete IL-17 (IL-17 γδT cells) and Foxp3+ γδT cells in lung tissues and then measured the content of IL-17 in the bronchoalveolar lavage fluid (BALF) by ELISA.Results Exposure to M. vaccae increased and decreased the relative proportions of Foxp3+ γδT cells and IL-17+ γδT cells, respectively, thereby decreasing airway reactivity and inflammation levels in asthmatic mice, and significantly decreasing IL-17 levels in BALF. Furthermore, mice treated with these primed T cells showed a decrease in IL-17+ γδT cells, and a concomitant increase in Foxp3+ γδT cells in their lung tissues. Furthermore, adoptive transfer of M. vaccae-primed γδT cells decreased GATA3 and NICD and increased T-bet in lung.Conclusions The M. vaccae-primed γδT cells alleviated the symptoms of asthma by reversing Th2 polarization in the lungs and inhibiting the Notch/GATA3 pathway.

Integrated relationship of nasopharyngeal airway host response and microbiome associates with bronchiolitis severity

Bronchiolitis is a leading cause of infant hospitalizations but its immunopathology remains poorly understood. Here we present data from 244 infants hospitalized with bronchiolitis in a multicenter prospective study, assessing the host response (transcriptome), microbial composition, and microbial function (metatranscriptome) in the nasopharyngeal airway, and associate them with disease severity. We investigate individual associations with disease severity identify host response, microbial taxonomical, and microbial functional modules by network analyses. We also determine the integrated relationship of these modules with severity. Several modules are significantly associated with risks of positive pressure ventilation use, including the host-type I interferon, neutrophil/interleukin-1, T cell regulation, microbial-branched-chain amino acid metabolism, and nicotinamide adenine dinucleotide hydrogen modules. Taken together, we show complex interplays between host and microbiome, and their contribution to disease severity.

Blockade of Tyrosine Kinase, LCK Leads to Reduction in Airway Inflammation through Regulation of Pulmonary Th2/Treg Balance and Oxidative Stress in Cockroach Extract-Induced Mouse Model of Allergic Asthma.

Asthma is one of the most common inflammatory diseases affecting the airways. Approximately 300 million individuals suffer from asthma around the world. Allergic immune responses in the asthmatic airways are predominantly driven by Th2 cells and eosinophils. Lymphocyte-specific protein tyrosine kinase (LCK) is a non-receptor tyrosine kinase which regulates several key intracellular events through phosphorylation of its substrates. Some of the intracellular signaling pathways activated by LCK phosphorylation help in differentiation of Th2 cells which secrete allergic cytokines that amplify airway inflammation. Therefore, this investigative study was designed to determine the role of LCK in a cockroach extract (CE)-induced airway inflammation murine model of allergic asthma. Further, the effect of a pharmacological LCK inhibitor, A-770041, on allergic airway inflammation and key intracellular pathways in CD4+ T cells was assessed. Our data exhibit that there is an activation of LCK during allergic airway inflammation as depicted by increased p-LCK levels in CD4+ T cells. Activated LCK is involved in the activation of ITK, PLC-γ, GATA3, NFkB, and NFATc1. Activated LCK is also involved in the upregulation of Th2 related cytokines, such as IL-4/IL-5/IL-13 and oxidative stress, and the downregulation of Treg cells. Furthermore, utilization of LCK inhibitor causes the reduction in p-LCK, PLC-γ, GATA3, and NFATc1 as well as Th2 cytokines and oxidative stress. LCK inhibitor causes upregulation of Treg cells in allergic mice. LCK inhibitor also caused a reduction in CE-induced airway inflammation and mucus secretion. Therefore, the inhibition of LCK signaling could be a fruitful approach to adjust allergic airway inflammation through the attuning of Th2/Treg immune responses. This study could lead to the design of newer treatment options for better management of allergic inflammation in asthma.