Browsing by Author "Tighe, Robert M"

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    A novel role for primary cilia in airway remodeling.
    (American journal of physiology. Lung cellular and molecular physiology, 2017-08) Trempus, Carol S; Song, Weifeng; Lazrak, Ahmed; Yu, Zhihong; Creighton, Judy R; Young, Bethany M; Heise, Rebecca L; Yu, Yen Rei; Ingram, Jennifer L; Tighe, Robert M; Matalon, Sadis; Garantziotis, Stavros
    Primary cilia (PC) are solitary cellular organelles that play critical roles in development, homeostasis, and disease pathogenesis by modulating key signaling pathways such as Sonic Hedgehog and calcium flux. The antenna-like shape of PC enables them also to facilitate sensing of extracellular and mechanical stimuli into the cell, and a critical role for PC has been described for mesenchymal cells such as chondrocytes. However, nothing is known about the role of PC in airway smooth muscle cells (ASMCs) in the context of airway remodeling. We hypothesized that PC on ASMCs mediate cell contraction and are thus integral in the remodeling process. We found that PC are expressed on ASMCs in asthmatic lungs. Using pharmacological and genetic methods, we demonstrated that PC are necessary for ASMC contraction in a collagen gel three-dimensional model both in the absence of external stimulus and in response to the extracellular component hyaluronan. Mechanistically, we demonstrate that the effect of PC on ASMC contraction is, to a small extent, due to their effect on Sonic Hedgehog signaling and, to a larger extent, due to their effect on calcium influx and membrane depolarization. In conclusion, PC are necessary for the development of airway remodeling by mediating calcium flux and Sonic Hedgehog signaling.
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    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, Monica

    Rationale

    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.
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    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 L

    Background

    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.
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    Inhalation of an RNA aptamer that selectively binds extracellular histones protects from acute lung injury.
    (Molecular therapy. Nucleic acids, 2023-03) Lei, Beilei; Wang, Chaojian; Snow, Kamie; Graton, Murilo E; Tighe, Robert M; Fager, Ammon M; Hoffman, Maureane R; Giangrande, Paloma H; Miller, Francis J
    Acute lung injury (ALI) is a syndrome of acute inflammation, barrier disruption, and hypoxemic respiratory failure associated with high morbidity and mortality. Diverse conditions lead to ALI, including inhalation of toxic substances, aspiration of gastric contents, infection, and trauma. A shared mechanism of acute lung injury is cellular toxicity from damage-associated molecular patterns (DAMPs), including extracellular histones. We recently described the selection and efficacy of a histone-binding RNA aptamer (HBA7). The current study aimed to identify the effects of extracellular histones in the lung and determine if HBA7 protected mice from ALI. Histone proteins decreased metabolic activity, induced apoptosis, promoted proinflammatory cytokine production, and caused endothelial dysfunction and platelet activation in vitro. HBA7 prevented these effects. The oropharyngeal aspiration of histone proteins increased neutrophil and albumin levels in bronchoalveolar lavage fluid (BALF) and precipitated neutrophil infiltration, interstitial edema, and barrier disruption in alveoli in mice. Similarly, inhaling wood smoke particulate matter, as a clinically relevant model, increased lung inflammation and alveolar permeability. Treatment by HBA7 alleviated lung injury in both models of ALI. These findings demonstrate the pulmonary delivery of HBA7 as a nucleic acid-based therapeutic for ALI.
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    Interstitial lung disease in a veterans affairs regional network; a retrospective cohort study.
    (PloS one, 2021-01) Bedoya, Armando; Pleasants, Roy A; Boggan, Joel C; Seaman, Danielle; Reihman, Anne; Howard, Lauren; Kundich, Robert; Welty-Wolf, Karen; Tighe, Robert M

    Background

    The epidemiology of Interstitial Lung Diseases (ILD) in the Veterans Health Administration (VHA) is presently unknown.

    Research question

    Describe the incidence/prevalence, clinical characteristics, and outcomes of ILD patients within the Veteran's Administration Mid-Atlantic Health Care Network (VISN6).

    Study design and methods

    A multi-center retrospective cohort study was performed of veterans receiving hospital or outpatient ILD care from January 1, 2008 to December 31st, 2015 in six VISN6 facilities. Patients were identified by at least one visit encounter with a 515, 516, or other ILD ICD-9 code. Demographic and clinical characteristics were summarized using median, 25th and 75th percentile for continuous variables and count/percentage for categorical variables. Characteristics and incidence/prevalence rates were summarized, and stratified by ILD ICD-9 code. Kaplan Meier curves were generated to define overall survival.

    Results

    3293 subjects met the inclusion criteria. 879 subjects (26%) had no evidence of ILD following manual medical record review. Overall estimated prevalence in verified ILD subjects was 256 per 100,000 people with a mean incidence across the years of 70 per 100,000 person-years (0.07%). The prevalence and mean incidence when focusing on people with an ILD diagnostic code who had a HRCT scan or a bronchoscopic or surgical lung biopsy was 237 per 100,000 people (0.237%) and 63 per 100,000 person-years respectively (0.063%). The median survival was 76.9 months for 515 codes, 103.4 months for 516 codes, and 83.6 months for 516.31.

    Interpretation

    This retrospective cohort study defines high ILD incidence/prevalence within the VA. Therefore, ILD is an important VA health concern.
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    The Eyes Have It-for Idiopathic Pulmonary Fibrosis: a Preliminary Observation.
    (Pulmonary therapy, 2022-09) Pleasants, Roy A; Bedoya, Armando D; Boggan, Joel M; Welty-Wolf, Karen; Tighe, Robert M

    Introduction

    The disease origins of idiopathic pulmonary fibrosis (IPF), which occurs at higher rates in certain races/ethnicities, are not understood. The highest rates occur in white persons of European descent, particularly those with light skin, who are also susceptible to lysosomal organelle dysfunction of the skin leading to fibroproliferative disease . We had observed clinically that the vast majority of patients with IPF had light-colored eyes, suggesting a phenotypic characteristic.

    Methods

    We pursued this observation through a research database from the USA Veterans Administration, a population that has a high occurrence of IPF due to predominance of elderly male smokers. Using this medical records database, which included facial photos, we compared the frequency of light (blue, green, hazel) and dark (light brown, brown) eyes among white patients diagnosed with IPF compared with a control group of lung granuloma only (no other radiologic evidence of interstitial lung disease).

    Results

    Light eye color was significantly more prevalent in patients with IPF than in the control group with lung granuloma [114/147 (77.6%) versus 129/263 (49.0%], p < 0.001), indicating that light-colored eyes are a phenotype associated with IPF .

    Conclusion

    We provide evidence that light eye color is predominant among white persons with IPF.
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    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 L

    Introduction

    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.
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    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 M
    Elevated 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.