Browsing by Author "Que, Loretta G"
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Item Open Access Asthma, Airflow Obstruction, and Eosinophilic Airway Inflammation Prevalence in Western Kenya: A Population-Based Cross-Sectional Study.(International journal of public health, 2023-01) Navuluri, Neelima; Lagat, David; Egger, Joseph R; Birgen, Elcy; Diero, Lameck; Murdoch, David M; Thielman, Nathan; Kussin, Peter S; Que, Loretta G; Paul, DevonObjectives: Determine the prevalence of airway disease (e.g., asthma, airflow obstruction, and eosinophilic airway inflammation) in Kenya, as well as related correlates of airway disease and health-related quality of life. Methods: A three-stage, cluster-randomized cross-sectional study in Uasin Gishu County, Kenya was conducted. Individuals 12 years and older completed questionnaires (including St. George's Respiratory Questionnaire for COPD, SGRQ-C), spirometry, and fractional exhaled nitric oxide (FeNO) testing. Prevalence ratios with 95% confidence intervals (CIs) were calculated. Multivariable models were used to assess correlates of airflow obstruction and high FeNO. Results: Three hundred ninety-two participants completed questionnaires, 369 completed FeNO testing, and 305 completed spirometry. Mean age was 37.5 years; 64% were women. The prevalence of asthma, airflow obstruction on spirometry, and eosinophilic airway inflammation was 21.7%, 12.3% and 15.7% respectively in the population. Women had significantly higher SGRQ-C scores compared to men (15.0 vs. 7.7). Wheezing or whistling in the last year and SGRQ-C scores were strongly associated with FeNO levels >50 ppb after adjusting for age, gender, BMI, and tobacco use. Conclusion: Airway disease is a significant health problem in Kenya affecting a young population who lack a significant tobacco use history.Item Open Access Clinical Trial of Losartan for Pulmonary Emphysema: Pulmonary Trials Cooperative LEEP Trial.(American journal of respiratory and critical care medicine, 2022-06) Wise, Robert A; Holbrook, Janet T; Brown, Robert H; Criner, Gerard J; Dransfield, Mark T; He, Jiaxian; Henderson, Robert J; Kaminsky, David A; Kaner, Robert J; Lazarus, Stephen C; Make, Barry J; McCormack, Meredith C; Neptune, Enid R; Que, Loretta GRationale
There are no pharmacologic agents that modify emphysema progression in patients with chronic obstructive pulmonary disease (COPD).Objective
Evaluate the efficacy of losartan, an angiotensin receptor blocker (ARB), to reduce emphysema progression.Methods
The trial was a multicenter randomized placebo-controlled trial, conducted between May 2017 and January 2021. Eligible participants were age ≥40, had moderate to severe airflow obstruction, ≥10 pack-years smoking, mild-moderate emphysema on high-resolution computed tomography (HRCT), and no medical indication for or intolerance of ARBs. Treatment with losartan, 100 mg daily, or matching placebo (1:1) was randomly assigned. The primary outcome was emphysema progression on HRCT over 48 weeks. Secondary outcomes included St George's Respiratory Questionnaire (SGRQ), modified Medical Research Council dyspnea scale, COPD Assessment Test, Physical Function-Short Form 20a (PROMIS 20a).Results
220 participants were enrolled; 58% were men, 19% were African American; and 24% current smokers. The medians (interquartile ranges) for age were as 65 (61, 73) years, and 48 (36, 59) for percent predicted FEV1 post-bronchodilator. The mean (95% confidence interval) percent emphysema progression was 1.35% (0.67, 2.03) in the losartan group vs 0.66% (0.09, 1.23) in placebo (P = NS).Conclusions
Losartan did not prevent emphysema progression in people with COPD with mild-moderate emphysema. Clinical trial registration available at www.Clinicaltrials
gov, ID: NCT02696564.Item Open Access Combining Heparin and a FX/Xa Aptamer to Reduce Thrombin Generation in Cardiopulmonary Bypass and COVID-19.(Nucleic acid therapeutics, 2022-01-12) Chabata, Charlene V; Frederiksen, James W; Olson, Lyra B; Naqvi, Ibtehaj A; Hall, Sharon E; Gunaratne, Ruwan; Kraft, Bryan D; Que, Loretta G; Chen, Lingye; Sullenger, Bruce AKnown limitations of unfractionated heparin (UFH) have encouraged the evaluation of anticoagulant aptamers as alternatives to UFH in highly procoagulant settings such as cardiopulmonary bypass (CPB). Despite progress, these efforts have not been totally successful. We take a different approach and explore whether properties of an anticoagulant aptamer can complement UFH, rather than replace it, to address shortcomings with UFH use. Combining RNA aptamer 11F7t, which targets factor X/Xa, with UFH (or low molecular weight heparin) yields a significantly enhanced anticoagulant cocktail effective in normal and COVID-19 patient blood. This aptamer-UFH combination (1) supports continuous circulation of human blood through an ex vivo membrane oxygenation circuit, as is required for patients undergoing CPB and COVID-19 patients requiring extracorporeal membrane oxygenation, (2) allows for a reduced level of UFH to be employed, (3) more effectively limits thrombin generation compared to UFH alone, and (4) is rapidly reversed by the administration of protamine sulfate, the standard treatment for reversing UFH clinically following CPB. Thus, the combination of factor X/Xa aptamer and UFH has significantly improved anticoagulant properties compared to UFH alone and underscores the potential of RNA aptamers to improve medical management of acute care patients requiring potent yet rapidly reversible anticoagulation.Item Open Access Control of antiviral innate immune response by protein geranylgeranylation(Science Advances, 2019-05) Yang, Shigao; Harding, Alfred T; Sweeney, Catherine; Miao, David; Swan, Gregory; Zhou, Connie; Jiang, Zhaozhao; Fitzgerald, Katherine A; Hammer, Gianna; Bergo, Martin O; Kroh, Heather K; Lacy, D Borden; Sun, Chunxiang; Glogauer, Michael; Que, Loretta G; Heaton, Nicholas S; Wang, DonghaiThe mitochondrial antiviral signaling protein (MAVS) orchestrates host antiviral innate immune response to RNA virus infection. However, how MAVS signaling is controlled to eradicate virus while preventing self-destructive inflammation remains obscure. Here, we show that protein geranylgeranylation, a posttranslational lipid modification of proteins, limits MAVS-mediated immune signaling by targeting Rho family small guanosine triphosphatase Rac1 into the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) at the mitochondria-ER junction. Protein geranylgeranylation and subsequent palmitoylation promote Rac1 translocation into MAMs upon viral infection. MAM-localized Rac1 limits MAVS’ interaction with E3 ligase Trim31 and hence inhibits MAVS ubiquitination, aggregation, and activation. Rac1 also facilitates the recruitment of caspase-8 and cFLIPL to the MAVS signalosome and the subsequent cleavage of Ripk1 that terminates MAVS signaling. Consistently, mice with myeloid deficiency of protein geranylgeranylation showed improved survival upon influenza A virus infection. Our work revealed a critical role of protein geranylgeranylation in regulating antiviral innate immune response.Item Open Access Dysregulated Metabolism in the Pathophysiology of Non-Allergic Obese Asthma.(Journal of asthma and allergy, 2021-01) McCravy, Matthew; Ingram, Jennifer L; Que, Loretta GAsthma is an obstructive airway disease that is characterized by reversible airway obstruction and is classically associated with atopic, TH2 driven inflammation. Landmark studies in the second half of the twentieth century identified eosinophils as a key mediator of inflammation and steroids, both inhaled and systemic, as a cornerstone of therapy. However, more recently other phenotypes of asthma have emerged that do not respond as well to traditional therapies. In particular, obese patients who develop asthma as adults are less likely to have eosinophilic airway inflammation and do not respond to traditional therapies. Obese patients often have metabolic comorbidities such as impaired glucose tolerance and dyslipidemias, also known as metabolic syndrome (MetS). The unified pathophysiology of metabolic syndrome is not known, however, several signaling pathways, such as the neuropeptide glucagon-like peptide-1 (GLP-1) and nitric oxide (NO) signaling have been shown to be dysregulated in MetS. These pathways are targeted by commercially available medications. This review discusses the potential roles that dysregulation of the GLP-1 and NO signaling pathways, along with arginine metabolism, play in the development of asthma in obese patients. GLP-1 receptors are found in high density in the lung and are also detectable in bronchoalveolar lavage fluid. NO has long been associated with asthma. We hypothesize that these derangements in metabolic signaling pathways underpin the asthmatic phenotype seen in obese patients with non-eosinophilic airway inflammation and poor response to established therapies. While still an active area of research, novel interventions are needed for this subset of patient who respond poorly to available asthma therapies.Item Open Access Effect of the S-nitrosoglutathione reductase inhibitor N6022 on bronchial hyperreactivity in asthma.(Immunity, inflammation and disease, 2018-06) Que, Loretta G; Yang, Zhonghui; Lugogo, Njira L; Katial, Rohit K; Shoemaker, Steven A; Troha, Janice M; Rodman, David M; Tighe, Robert M; Kraft, MonicaRationale
Patients with asthma demonstrate depletion of the endogenous bronchodilator GSNO and upregulation of GSNOR.Objectives
An exploratory proof of concept clinical study of N6022 in mild asthma to determine the potential bronchoprotective effects of GSNOR inhibition. Mechanistic studies aimed to provide translational evidence of effect.Methods
Fourteen mild asthma patients were treated with intravenous N6022 (5 mg) or placebo and observed for 7 days, with repeated assessments of the provocative dose of methacholine causing a 20% fall in FEV1 (methacholine PC20 FEV1), followed by a washout period and crossover treatment and observation. In vitro studies in isolated eosinophils investigated the effect of GSNO and N6022 on apoptosis.Measurements and main results
This was a negative trial as it failed to reach its primary endpoint, which was change from baseline in methacholine PC20 FEV1 at 24 h. However, our exploratory analysis demonstrated significantly more two dose-doubling increases in PC20 FEV1 for N6022 compared with placebo (21% vs 6%, P < 0.05) over the 7-day observation period. Furthermore, a significant treatment effect was observed in the change in PC20 FEV1 from baseline averaged over the 7-day observation period (mean change: +0.82 mg/ml [N6022] from 1.34 mg/ml [baseline] vs -0.18 mg/ml [placebo] from 1.16 mg/ml [baseline], P = 0.023). N6022 was well tolerated in mild asthmatics. In vitro studies demonstrated enhanced eosinophilic apoptosis with N6022.Conclusions
In this early phase exploratory proof of concept trial in asthma, N6022 did not significantly alter methacholine PC20 FEV1 at 24 h, but did have a treatment effect at 7 days compared to baseline. Further investigation of the efficacy of S-nitrosoglutathione reductase inhibition in a patient population with eosinophilic asthma is warranted.Item Open Access Effects of Oxidative Stress on Airway Epithelium Permeability in Asthma and Potential Implications for Patients with Comorbid Obesity.(Journal of asthma and allergy, 2023-01) Kim, Haein R; Ingram, Jennifer L; Que, Loretta G20 million adults and 4.2 million children in the United States have asthma, a disease resulting in inflammation and airway obstruction in response to various factors, including allergens and pollutants and nonallergic triggers. Obesity, another highly prevalent disease in the US, is a major risk factor for asthma and a significant cause of oxidative stress throughout the body. People with asthma and comorbid obesity are susceptible to developing severe asthma that cannot be sufficiently controlled with current treatments. More research is needed to understand how asthma pathobiology is affected when the patient has comorbid obesity. Because the airway epithelium directly interacts with the outside environment and interacts closely with the immune system, understanding how the airway epithelium of patients with asthma and comorbid obesity is altered compared to that of lean asthma patients will be crucial for developing more effective treatments. In this review, we discuss how oxidative stress plays a role in two chronic inflammatory diseases, obesity and asthma, and propose a mechanism for how these conditions may compromise the airway epithelium.Item Open Access Exogenous leptin enhances markers of airway fibrosis in a mouse model of chronic allergic airways disease.(Respiratory research, 2022-05-24) Ihrie, Mark D; McQuade, Victoria L; Womble, Jack T; Hegde, Akhil; McCravy, Matthew S; Lacuesta, Cyrus Victor G; Tighe, Robert M; Que, Loretta G; Walker, Julia KL; Ingram, Jennifer LBackground
Asthma patients with comorbid obesity exhibit increased disease severity, in part, due to airway remodeling, which is also observed in mouse models of asthma and obesity. A mediator of remodeling that is increased in obesity is leptin. We hypothesized that in a mouse model of allergic airways disease, mice receiving exogenous leptin would display increased airway inflammation and fibrosis.Methods
Five-week-old male and female C57BL/6J mice were challenged with intranasal house dust mite (HDM) allergen or saline 5 days per week for 6 weeks (n = 6-9 per sex, per group). Following each HDM exposure, mice received subcutaneous recombinant human leptin or saline. At 48 h after the final HDM challenge, lung mechanics were evaluated and the mice were sacrificed. Bronchoalveolar lavage was performed and differential cell counts were determined. Lung tissue was stained with Masson's trichrome, periodic acid-Schiff, and hematoxylin and eosin stains. Mouse lung fibroblasts were cultured, and whole lung mRNA was isolated.Results
Leptin did not affect mouse body weight, but HDM+leptin increased baseline blood glucose. In mixed-sex groups, leptin increased mouse lung fibroblast invasiveness and increased lung Col1a1 mRNA expression. Total lung resistance and tissue damping were increased with HDM+leptin treatment, but not leptin or HDM alone. Female mice exhibited enhanced airway responsiveness to methacholine with HDM+leptin treatment, while leptin alone decreased total respiratory system resistance in male mice.Conclusions
In HDM-induced allergic airways disease, administration of exogenous leptin to mice enhanced lung resistance and increased markers of fibrosis, with differing effects between males and females.Item Open Access Immuno-fibrotic drivers of impaired lung function in post-COVID-19 syndrome.(medRxiv, 2021-02-06) Chun, Hyung J; Coutavas, Elias; Pine, Alexander; Lee, Alfred I; Yu, Vanessa; Shallow, Marcus; Giovacchini, Coral X; Mathews, Anne; Stephenson, Brian; Que, Loretta G; Lee, Patty J; Kraft, Bryan DIntroduction: Subjects recovering from COVID-19 frequently experience persistent respiratory ailments; however, little is known about the underlying biological factors that may direct lung recovery and the extent to which these are affected by COVID-19 severity. Methods: We performed a prospective cohort study of subjects with persistent symptoms after recovering from acute COVID-19 illness, collecting clinical data, pulmonary function tests, and blood. Plasma samples were used for multiplex profiling of circulating factors associated with inflammation, metabolism, angiogenesis, and fibrosis. Results: Sixty-one subjects were enrolled across two academic medical centers at a median of 9 weeks (interquartile range 6-10) after COVID-19 illness: n=13 subjects (21%) mild/non-hospitalized, n=30 (49%) hospitalized/non-critical, and n=18 subjects (30%) hospitalized/intensive care ("ICU"). Fifty-three subjects (85%) had lingering symptoms, most commonly dyspnea (69%) and cough (58%). Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and diffusing capacity for carbon monoxide (DLCO) declined as COVID-19 severity increased (P<0.05), but did not correlate with respiratory symptoms. Partial least-squares discriminant analysis of plasma biomarker profiles clustered subjects by past COVID-19 severity. Lipocalin 2 (LCN2), matrix metalloproteinase-7 (MMP-7), and hepatocyte growth factor (HGF) identified by the model were significantly higher in the ICU group (P<0.05) and inversely correlated with FVC and DLCO (P<0.05). Conclusions: Subjective respiratory symptoms are common after acute COVID-19 illness but do not correlate with COVID-19 severity or pulmonary function. Host response profiles reflecting neutrophil activation (LCN2), fibrosis signaling (MMP-7), and alveolar repair (HGF) track with lung impairment and may be novel therapeutic or prognostic targets. Funding: The study was funded in part by the NHLBI (K08HL130557 to BDK and R01HL142818 to HJC), the DeLuca Foundation Award (AP), a donation from Jack Levin to the Benign Hematology Program at Yale, and Divisional/Departmental funds from Duke University.Item Open Access Immunofibrotic drivers of impaired lung function in postacute sequelae of SARS-CoV-2 infection.(JCI insight, 2021-07-22) Chun, Hyung J; Coutavas, Elias; Pine, Alexander B; Lee, Alfred I; Yu, Vanessa L; Shallow, Marcus K; Giovacchini, Coral X; Mathews, Anne M; Stephenson, Brian; Que, Loretta G; Lee, Patty J; Kraft, Bryan DBACKGROUNDIndividuals recovering from COVID-19 frequently experience persistent respiratory ailments, which are key elements of postacute sequelae of SARS-CoV-2 infection (PASC); however, little is known about the underlying biological factors that may direct lung recovery and the extent to which these are affected by COVID-19 severity.METHODSWe performed a prospective cohort study of individuals with persistent symptoms after acute COVID-19, collecting clinical data, pulmonary function tests, and plasma samples used for multiplex profiling of inflammatory, metabolic, angiogenic, and fibrotic factors.RESULTSSixty-one participants were enrolled across 2 academic medical centers at a median of 9 weeks (interquartile range, 6-10 weeks) after COVID-19 illness: n = 13 participants (21%) had mild COVID-19 and were not hospitalized, n = 30 participants (49%) were hospitalized but were considered noncritical, and n = 18 participants (30%) were hospitalized and in the intensive care unit (ICU). Fifty-three participants (85%) had lingering symptoms, most commonly dyspnea (69%) and cough (58%). Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and diffusing capacity for carbon monoxide (DLCO) declined as COVID-19 severity increased (P < 0.05) but these values did not correlate with respiratory symptoms. Partial least-squares discriminant analysis of plasma biomarker profiles clustered participants by past COVID-19 severity. Lipocalin-2 (LCN2), MMP-7, and HGF identified by our analysis were significantly higher in the ICU group (P < 0.05), inversely correlated with FVC and DLCO (P < 0.05), and were confirmed in a separate validation cohort (n = 53).CONCLUSIONSubjective respiratory symptoms are common after acute COVID-19 illness but do not correlate with COVID-19 severity or pulmonary function. Host response profiles reflecting neutrophil activation (LCN2), fibrosis signaling (MMP-7), and alveolar repair (HGF) track with lung impairment and may be novel therapeutic or prognostic targets.FundingNational Heart, Lung, and Blood Institute (K08HL130557 and R01HL142818), American Heart Association (Transformational Project Award), the DeLuca Foundation Award, a donation from Jack Levin to the Benign Hematology Program at Yale University, and Duke University.Item Open Access Key Pathogenic Factors in Coronavirus Disease 2019-Associated Coagulopathy and Acute Lung Injury Highlighted in a Patient With Copresentation of Acute Myelocytic Leukemia: A Case Report.(A&A practice, 2021-03-30) Olson, Lyra B; Naqvi, Ibtehaj A; Turner, Daniel J; Morrison, Sarah A; Kraft, Bryan D; Chen, Lingye; Sullenger, Bruce A; Nair, Smita K; Que, Loretta G; Levy, Jerrold HThe role of concurrent illness in coronavirus disease 2019 (COVID-19) is unknown. Patients with leukemia may display altered thromboinflammatory responses. We report a 53-year-old man presenting with acute leukemia and COVID-19 who developed thrombotic complications and acute respiratory distress syndrome. Multiple analyses, including rotational thromboelastometry and flow cytometry on blood and bronchoalveolar lavage, are reported to characterize coagulation and immune profiles. The patient developed chemotherapy-induced neutropenia that may have protected his lungs from granulocyte-driven hyperinflammatory acute lung injury. However, neutropenia also alters viral clearing, potentially enabling ongoing viral propagation. This case depicts a precarious equilibrium between leukemia and COVID-19.Item Open Access Obesity and Asthma.(Seminars in respiratory and critical care medicine, 2022-02-17) Dixon, Anne E; Que, Loretta GObesity is a major risk factor for the development of asthma, and the prevalence of obesity is higher in people with asthma than in the general population. Obese people often have severe asthma-recent studies in the United States suggest that 60% of adults with severe asthma are obese. Multiple mechanisms link obesity and asthma, which are discussed in this article, and these pathways contribute to different phenotypes of asthma among people with obesity. From a practical aspect, changes in physiology and immune markers affect diagnosis and monitoring of disease activity in people with asthma and obesity. Obesity also affects response to asthma medications and is associated with an increased risk of co-morbidities such as gastroesophageal reflux disease, depression, and obstructive sleep apnea, all of which may affect asthma control. Obese people may be at elevated risk of exacerbations related to increased risk of severe disease in response to viral infections. Interventions that target improved dietary quality, exercise, and weight loss are likely to be particularly helpful for this patient population.Item Open Access Oxygen delivery systems for adults in Sub-Saharan Africa: A scoping review.(Journal of global health, 2021-05-08) Navuluri, Neelima; Srour, Maria L; Kussin, Peter S; Murdoch, David M; MacIntyre, Neil R; Que, Loretta G; Thielman, Nathan M; McCollum, Eric DBackground
Respiratory diseases are the leading cause of death and disability worldwide. Oxygen is an essential medicine used to treat hypoxemia from respiratory diseases. However, the availability and utilization of oxygen delivery systems for adults in sub-Saharan Africa is not well-described. We aim to identify and describe existing data around oxygen availability and provision for adults in sub-Saharan Africa, determine knowledge or research gaps, and make recommendations for future research and capacity building.Methods
We systematically searched four databases for articles on April 22, 2020, for variations of keywords related to oxygen with a focus on countries in sub-Saharan Africa. Inclusion criteria were studies that included adults and addressed hypoxemia assessment or outcome, oxygen delivery mechanisms, oxygen availability, oxygen provision infrastructure, and oxygen therapy and outcomes.Results
35 studies representing 22 countries met inclusion criteria. Availability of oxygen delivery systems ranged from 42%-94% between facilities, with wide variability in the consistency of availability. There was also wide reported prevalence of hypoxemia, with most studies focusing on specific populations. In facilities where oxygen is available, health care workers are ill-equipped to identify adult patients with hypoxemia, provide oxygen to those who need it, and titrate or discontinue oxygen appropriately. Oxygen concentrators were shown to be the most cost-effective delivery system in areas where power is readily available.Conclusions
There is a substantial need for building capacity for oxygen delivery throughout sub-Saharan Africa. Addressing this critical issue will require innovation and a multi-faceted approach of developing infrastructure, better equipping facilities, and health care worker training.Item Open Access Prevalence and phenotypic trajectories of hypoxaemia among hospitalised adults in Kenya: a single-centre, prospective cohort study.(BMJ open, 2023-09) Navuluri, Neelima; Lagat, David K; Birgen, Elcy; Kitur, Sylvia; Kussin, Peter S; Murdoch, David M; Thielman, Nathan M; Parish, Alice; Green, Cynthia L; MacIntyre, Neil; Egger, Joseph R; Wools-Kaloustian, Kara; Que, Loretta GObjective
Global medical oxygen security is limited by knowledge gaps in hypoxaemia burden and oxygen access in low-income and middle-income countries. We examined the prevalence and phenotypic trajectories of hypoxaemia among hospitalised adults in Kenya, with a focus on chronic hypoxaemia.Design
Single-centre, prospective cohort study.Setting
National tertiary referral hospital in Eldoret, Kenya between September 2019 and April 2022.Participants
Adults (age ≥18 years) admitted to general medicine wards.Primary and secondary outcome measures
Our primary outcome was proportion of patients who were hypoxaemic (oxygen saturation, SpO2 ≤88%) on admission. Secondary outcomes were proportion of patients with hypoxaemia on admission who had hypoxaemia resolution, hospital discharge, transfer, or death among those with unresolved hypoxaemia or chronic hypoxaemia. Patients remaining hypoxaemic for ≤3 days after admission were enrolled into an additional cohort to determine chronic hypoxaemia. Chronic hypoxaemia was defined as an SpO2 ≤ 88% at either 1-month post-discharge follow-up or, for patients who died prior to follow-up, a documented SpO2 ≤88% during a previous hospital discharge or outpatient visit within the last 6 months.Results
We screened 4104 patients (48.5% female, mean age 49.4±19.4 years), of whom 23.8% were hypoxaemic on admission. Hypoxaemic patients were significantly older and more predominantly female than normoxaemic patients. Among those hypoxaemic on admission, 33.9% had resolution of their hypoxaemia as inpatients, 55.6% had unresolved hypoxaemia (31.0% died before hospital discharge, 13.3% were alive on discharge and 11.4% were transferred) and 10.4% were lost to follow-up. The prevalence of chronic hypoxaemia was 2.1% in the total screened population, representing 8.8% of patients who were hypoxaemic on admission. Chronic hypoxaemia was determined at 1-month post-discharge among 59/86 patients and based on prior documentation among 27/86 patients.Conclusion
Hypoxaemia is highly prevalent among adults admitted to a general medicine ward at a national referral hospital in Kenya. Nearly 1 in 11 patients who are hypoxaemic on admission are chronically hypoxaemic.Item Open Access SHP-1 as a critical regulator of Mycoplasma pneumoniae-induced inflammation in human asthmatic airway epithelial cells.(Journal of immunology (Baltimore, Md. : 1950), 2012-04) Wang, Ying; Zhu, Zhou; Church, Tony D; Lugogo, Njira L; Que, Loretta G; Francisco, Dave; Ingram, Jennifer L; Huggins, Molly; Beaver, Denise M; Wright, Jo Rae; Kraft, MonicaAsthma is a chronic inflammatory disease in which airway epithelial cells are the first line of defense against exposure of the airway to infectious agents. Src homology protein (SHP)-1, a protein tyrosine phosphatase, is a negative regulator of signaling pathways that are critical to the development of asthma and host defense. We hypothesize that SHP-1 function is defective in asthma, contributing to the increased inflammatory response induced by Mycoplasma pneumoniae, a pathogen known to exacerbate asthma. M. pneumoniae significantly activated SHP-1 in airway epithelial cells collected from nonasthmatic subjects by bronchoscopy with airway brushing but not in cells from asthmatic subjects. In asthmatic airway epithelial cells, M. pneumoniae induced significant PI3K/Akt phosphorylation, NF-κB activation, and IL-8 production compared with nonasthmatic cells, which were reversed by SHP-1 overexpression. Conversely, SHP-1 knockdown significantly increased IL-8 production and PI3K/Akt and NF-κB activation in the setting of M. pneumoniae infection in nonasthmatic cells, but it did not exacerbate these three parameters already activated in asthmatic cells. Thus, SHP-1 plays a critical role in abrogating M. pneumoniae-induced IL-8 production in nonasthmatic airway epithelial cells through inhibition of PI3K/Akt and NF-κB activity, but it is defective in asthma, resulting in an enhanced inflammatory response to infection.Item Open Access Use of Fractional Exhaled Nitric Oxide to Guide the Treatment of Asthma An Official American Thoracic Society Clinical Practice Guideline: Executive Summary(AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2021-11-15) Khatri, Sumita B; Laccarino, Jonathan M; Barochia, Amisha; Soghier, Israa; Akuthota, Praveen; Brady, Anna; Covar, Ronina A; Debley, Jason S; Diamant, Zuzana; Fitzpatrick, Anne M; Kaminsky, David A; Kenyon, Nicholas J; Khurana, Sandhya; Lipworth, Brian J; McCarthy, Kevin; Peters, Michael; Que, Loretta G; Ross, Kristie R; Schneider-Futschik, Elena K; Sorkness, Christine A; Hallstrand, Teal SItem Open Access Vertical sleeve gastrectomy associates with airway hyperresponsiveness in a murine model of allergic airway disease and obesity.(Frontiers in endocrinology, 2023-01) Womble, Jack T; Ihrie, Mark D; McQuade, Victoria L; Hegde, Akhil; McCravy, Matthew S; Phatak, Sanat; Tighe, Robert M; Que, Loretta G; D'Alessio, David; Walker, Julia KL; Ingram, Jennifer LIntroduction
Asthma is a chronic airway inflammatory disease marked by airway inflammation, remodeling and hyperresponsiveness to allergens. Allergic asthma is normally well controlled through the use of beta-2-adrenergic agonists and inhaled corticosteroids; however, a subset of patients with comorbid obesity experience resistance to currently available therapeutics. Patients with asthma and comorbid obesity are also at a greater risk for severe disease, contributing to increased risk of hospitalization. Bariatric surgery improves asthma control and airway hyperresponsiveness in patients with asthma and comorbid obesity, however, the underlying mechanisms for these improvements remain to be elucidated. We hypothesized that vertical sleeve gastrectomy (VSG), a model of metabolic surgery in mice, would improve glucose tolerance and airway inflammation, resistance, and fibrosis induced by chronic allergen challenge and obesity.Methods
Male C57BL/6J mice were fed a high fat diet (HFD) for 13 weeks with intermittent house dust mite (HDM) allergen administration to induce allergic asthma, or saline as control. At week 11, a subset of mice underwent VSG or Sham surgery with one week recovery. A separate group of mice did not undergo surgery. Mice were then challenged with HDM or saline along with concurrent HFD feeding for 1-1.5 weeks before measurement of lung mechanics and harvesting of tissues, both of which occurred 24 hours after the final HDM challenge. Systemic and pulmonary cytokine profiles, lung histology and gene expression were analyzed.Results
High fat diet contributed to increased body weight, serum leptin levels and development of glucose intolerance for both HDM and saline treatment groups. When compared to saline-treated mice, HDM-challenged mice exhibited greater weight gain. VSG improved glucose tolerance in both saline and HDM-challenged mice. HDM-challenged VSG mice exhibited an increase in airway hyperresponsiveness to methacholine when compared to the non-surgery group.Discussion
The data presented here indicate increased airway hyperresponsiveness in allergic mice undergoing bariatric surgery.Item Open Access Wood smoke particle exposure in mice reduces the severity of influenza infection.(Toxicology and applied pharmacology, 2021-09) Vose, Aaron; McCravy, Matthew; Birukova, Anastasiya; Yang, Zhonghui; Hollingsworth, John W; Que, Loretta G; Tighe, Robert MElevated ambient temperatures and extreme weather events have increased the incidence of wildfires world-wide resulting in increased wood smoke particle (WSP). Epidemiologic data suggests that WSP exposure associates with exacerbations of respiratory diseases, and with increased respiratory viral infections. To assess the impact of WSP exposure on host response to viral pneumonia, we performed WSP exposures in rodents followed by infection with mouse adapted influenza (HINI-PR8). C57BL/6 male mice aged 6-8 weeks were challenged with WSP or PBS by oropharyngeal aspiration in acute (single dose) or sub-acute exposures (day 1, 3, 5, 7 and 10). Additional groups underwent sub-acute exposure followed by infection by influenza or heat-inactivated (HI) virus. Following exposures/infection, bronchoalveolar lavage (BAL) was performed to assess for total cell counts/differentials, total protein, protein carbonyls and hyaluronan. Lung tissue was assessed for viral counts by real time PCR. When compared to PBS, acute WSP exposure associated with an increase in airspace macrophages. Alternatively, sub-acute exposure resulted in a dose dependent increase in airspace neutrophils. Sub-acute WSP exposure followed by influenza infection was associated with improved respiratory viral outcomes including reduced weight loss and increased blood oxygen saturation, and decreased protein carbonyls and viral titers. Flow cytometry demonstrated dynamic changes in pulmonary macrophage and T cell subsets based on challenge with WSP and influenza. This data suggests that sub-acute WSP exposure can improve host response to acute influenza infection.