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1.  Repeated Bouts of Moderate-Intensity Aerobic Exercise Reduce Airway Reactivity in a Murine Asthma Model 
We have reported that moderate-intensity aerobic exercise training attenuates airway inflammation in mice sensitized/challenged with ovalbumin (OVA). The current study determined the effects of repeated bouts of aerobic exercise at a moderate intensity on airway hyperresponsiveness (AHR) in these mice. Mice were sensitized/challenged with OVA or saline and exercised at a moderate intensity 3 times/week for 4 weeks. At protocol completion, mice were analyzed for changes in AHR via mechanical ventilation. Results show that exercise decreased total lung resistance 60% in OVA-treated mice as compared with controls; exercise also decreased airway smooth muscle (ASM) thickness. In contrast, exercise increased circulating epinephrine levels 3-fold in saline- and OVA-treated mice. Because epinephrine binds β2-adrenergic receptors (AR), which facilitate bronchodilatation, the role of β2-AR in exercise-mediated improvements in AHR was examined. Application of the β2-AR antagonist butoxamine HCl blocked the effects of exercise on lung resistance in OVA-treated mice. In parallel, ASM cells were examined for changes in the protein expression of β2-AR and G-protein receptor kinase-2 (GRK-2); GRK-2 promotes β2-AR desensitization. Exercise had no effect on β2-AR expression in ASM cells of OVA-treated mice; however, exercise decreased GRK-2 expression by 50% as compared with controls. Exercise also decreased prostaglandin E2 (PGE2) production 5-fold, but had no effect on E prostanoid-1 (EP1) receptor expression within the lungs of OVA-treated mice; both PGE2 and the EP1 receptor have been implicated in β2-AR desensitization. Together, these data indicate that moderate-intensity aerobic exercise training attenuates AHR via a mechanism that involves β2-AR.
doi:10.1165/rcmb.2009-0038OC
PMCID: PMC2822985  PMID: 19423772
asthma; airway hyperresponsiveness; exercise; β2-adrenergic receptor
2.  Repeated Bouts of Aerobic Exercise Enhance Regulatory T Cell Responses in a Murine Asthma Model 
Brain, behavior, and immunity  2009;24(1):153-159.
We have reported previously that moderate intensity aerobic exercise training attenuates airway inflammation in a murine asthma model. Recent studies implicate regulatory T (Treg) cells in decreasing asthma-related airway inflammation; as such, the current study examined the effect of exercise on Treg cell function in a murine asthma model. Mice were sensitized with ovalbumin (OVA) prior to the start of exercise training at a moderate intensity 3× / week for 4 wks; exercise was performed as treadmill running (13.5 m/min, 0% grade). Mice were OVA challenged repeatedly throughout the exercise protocol. At protocol completion, mice were analyzed for changes in the number and suppressive function of CD4+CD25+Foxp3+ cells isolated from lungs, mediastinal lymph nodes, and spleens. Results show that exercise increased significantly the number of Foxp3+ cells within the lungs and mediastinal lymph nodes, but not the spleens, of OVA-treated mice as compared with sedentary controls. Exercise also enhanced the suppression function of CD4+CD25+Foxp3+ Treg cells derived from OVA-treated mice as compared with sedentary controls. Specifically, Treg cells from exercised, OVA-treated mice more effectively suppressed CD4+CD25− cell proliferation and Th2 cytokine production in vitro. Enhanced suppression was associated with increased protein levels of TGF-β and lesser amounts of IL-10 and IL-17; however, blocking TGF-β had no effect on suppressive functions. These data demonstrate that exercise-mediated increases in Treg cell function may play a role in the attenuation of airway inflammation. Further, these results indicate that moderate intensity aerobic exercise training may alter the Treg cell function within the asthmatic airway.
doi:10.1016/j.bbi.2009.09.011
PMCID: PMC2787986  PMID: 19781626
Treg; asthma; aerobic exercise; regulatory T cells
3.  Epithelial cells as immune effector cells: The role of CD40 
Seminars in immunology  2009;21(5):289-292.
Through the expression of inflammatory mediators and immune-related molecules, epithelial cells function as immune effector cells in a wide-variety of tissues; the expression of the CD40 receptor on these cells contributes this role. Engagement of CD40 activates epithelial cells and results in their release of pro- and anti-inflammatory mediators as well as pro-fibrotic molecules. As such, epithelial CD40 has been implicated in the pathogenesis of inflammatory disorders, generation of self-tolerance, and rejection of allografts.
doi:10.1016/j.smim.2009.06.002
PMCID: PMC2749080  PMID: 19628407
5.  Aerobic Exercise Attenuates Airway Inflammatory Responses in a Mouse Model of Atopic Asthma 
Recent reports indicate that aerobic exercise improves the overall physical fitness and health of asthmatic patients. The specific exercise-induced improvements in the pathology of asthma and the mechanisms by which these improvements occur, however, are ill-defined; thus, the therapeutic potential of exercise in the treatment of asthma remains unappreciated. Using an OVA-driven mouse model, we examined the role of aerobic exercise in modulating inflammatory responses associated with atopic asthma. Data demonstrate that moderate intensity aerobic exercise training decreased leukocyte infiltration, cytokine production, adhesion molecule expression, and structural remodeling within the lungs of OVA-sensitized mice (n = 6–10; p < 0.05). Because the transcription factor NF-κB regulates the expression of a variety of genes that encode inflammatory mediators, we monitored changes in NF-κB activation in the lungs of exercised/sensitized mice. Results show that exercise decreased NF-κB nuclear translocation and IκBα phosphorylation, indicating that exercise decreased NF-κB activation in the lungs of sensitized mice (n = 6). Taken together, these results suggest that aerobic exercise attenuates airway inflammation in a mouse model of atopic asthma via modulation of NF-κB activation. Potential exists, therefore, for the amelioration of asthma-associated chronic airway inflammation through the use of aerobic exercise training as a non-drug therapeutic modality.
PMCID: PMC2892102  PMID: 15034069
6.  Acute Exercise Decreases Airway Inflammation, but Not Responsiveness, in an Allergic Asthma Model 
Previous studies have suggested that the asthmatic responses of airway inflammation, remodeling, and hyperresponsiveness (AHR) are interrelated; in this study, we used exercise to examine the nature of this interrelationship. Mice were sensitized and challenged with ovalbumin (OVA); mice were then exercised via running on a motorized treadmill at a moderate intensity. Data indicate that, within the lungs of OVA-treated mice, exercise attenuated the production of inflammatory mediators, including chemokines KC, RANTES, and MCP-1 and IL-12p40/p80. Coordinately, OVA-treated and exercised mice displayed decreases in leukocyte infiltration, including eosinophils, as compared with sedentary controls. Results also show that a single bout of exercise significantly decreased phosphorylation of the NFκB p65 subunit, which regulates the gene expression of a wide variety of inflammatory mediators. In addition, OVA-treated and exercised mice exhibited decreases in the levels of Th2-derived cytokines IL-5 and IL-13 and the prostaglandin PGE2, as compared with sedentary controls. In contrast, results show that a single bout of exercise had no effect on AHR in OVA-treated mice challenged with increasing doses of aerosolized methacholine (0–50 mg/ml) as compared with sedentary mice. Exercise also had no effect on epithelial cell hypertrophy, mucus production, or airway wall thickening in OVA-treated mice as compared with sedentary controls. These findings suggest that a single bout of aerobic exercise at a moderate intensity attenuates airway inflammation but not AHR or airway remodeling in OVA-treated mice. The implication of these findings for the interrelationship between airway inflammation, airway remodeling, and AHR is discussed.
doi:10.1165/rcmb.2008-0172OC
PMCID: PMC2606949  PMID: 18635813
asthma; aerobic exercise; airway inflammation; remodeling; hyperresponsiveness
7.  Use of the Cockroach Antigen Model of Acute Asthma to Determine the Immunomodulatory Role of Early Exposure to Gastrointestinal Infection 
Summary
The increased incidence of asthma over the last 50 years in developed countries has been associated with a decrease in infections acquired early in childhood. These early infections are thought to shape subsequent immune responses. Although there have been multiple clinical associations between gastrointestinal infections and decreased asthma incidence, it has been difficult to move beyond a simple correlation when studying human patients. This section describes an acute asthma model in C57BL/6 mice designed to specifically evaluate the effect of prior gastric Helicobacter colonization and inflammation in amurine model of cockroach allergen-induced asthma.
doi:10.1007/978-1-62703-496-8_21
PMCID: PMC4097169  PMID: 23943460
asthma; helicobacter; gastritis; murine; cockroach antigen; hygiene hypothesis; toll-like receptors; neonatal
8.  Free Radical-Producing Myeloid-Derived Regulatory Cells: Potent Activators and Suppressors of Lung Inflammation and Airway Hyperresponsiveness 
Mucosal immunology  2011;4(5):503-518.
Levels of reactive free radicals are elevated in the airway during asthmatic exacerbations, but their roles in the pathophysiology of asthma remain unclear. We have identified subsets of myeloid-derived suppressor-like cells as key sources of nitric oxide and superoxide in the lungs of mice with evolving experimental allergic airway inflammation and established these cells as master regulators of the airway inflammatory response. The profiles of free radicals they produced depended on expression of iNOS, arginase, and NADPH oxidase. These radicals controlled the pro- and anti-inflammatory potential of these cells, and also regulated the reciprocal pattern of their infiltration into the lung. The nitric oxide-producing cells were Ly-6C+Ly-6G− and down-modulated T cell activation, recruited Treg cells, and dramatically down-regulated antigen-induced airway hyperresponsiveness. The superoxide-producing cells were Ly-6C−Ly-6G+ and expressed proinflammatory activities, exacerbating airway hyperresponsiveness in a superoxide-dependent fashion. A smaller population of Ly-6C+Ly-6G+ cells also suppressed T cell responses, but in an iNOS- and arginase-independent fashion. These regulatory myeloid cells represent important targets for asthma therapy.
doi:10.1038/mi.2011.16
PMCID: PMC3694614  PMID: 21471960
9.  The ΔF508-CFTR mutation inhibits wild-type CFTR processing and function when co-expressed in human airway epithelia and in mouse nasal mucosa 
BMC Physiology  2012;12:12.
Background
Rescue or correction of CFTR function in native epithelia is the ultimate goal of CF therapeutics development. Wild-type (WT) CFTR introduction and replacement is also of particular interest. Such therapies may be complicated by possible CFTR self-assembly into an oligomer or multimer.
Results
Surprisingly, functional CFTR assays in native airway epithelia showed that the most common CFTR mutant, ΔF508-CFTR (ΔF-CFTR), inhibits WT-CFTR when both forms are co-expressed. To examine more mechanistically, both forms of CFTR were transfected transiently in varying amounts into IB3-1 CF human airway epithelial cells and HEK-293 human embryonic kidney cells null for endogenous CFTR protein expression. Increasing amounts of ΔF-CFTR inhibited WT-CFTR protein processing and function in CF human airway epithelial cells but not in heterologous HEK-293 cells. Stably expressed ΔF-CFTR in clones of the non-CF human airway epithelial cell line, CALU-3, also showed reduction in cAMP-stimulated anion secretion and in WT-CFTR processing. An ultimate test of this dominant negative-like effect of ΔF-CFTR on WT-CFTR was the parallel study of two different CF mouse models: the ΔF-CFTR mouse and the bitransgenic CFTR mouse corrected in the gut but null in the lung and airways. WT/ΔF heterozygotes had an intermediate phenotype with regard to CFTR agonist responses in in vivo nasal potential difference (NPD) recordings and in Ussing chamber recordings of short-circuit current (ISC) in vitro on primary tracheal epithelial cells isolated from the same mice. In contrast, CFTR bitransgenic +/− heterozygotes had no difference in their responses versus +/+ wild-type mice.
Conclusions
Taken altogether, these data suggest that ΔF-CFTR and WT-CFTR co-assemble into an oligomeric macromolecular complex in native epithelia and share protein processing machinery and regulation at the level of the endoplasmic reticulum (ER). As a consequence, ΔF-CFTR slows WT-CFTR protein processing and limits its expression and function in the apical membrane of native airway epithelia. Implications of these data for the relative health of CF heterozygous carriers, for CFTR protein processing in native airway epithelia, and for the relative efficacy of different CF therapeutic approaches is significant and is discussed.
doi:10.1186/1472-6793-12-12
PMCID: PMC3507716  PMID: 22999299
Cystic fibrosis (CF); CFTR; Biogenesis; CF heterozygote; Oligomer; Chloride ion channels
10.  Requisite role for the Dectin-1 beta-glucan receptor in pulmonary defense against Aspergillus fumigatus1 
Immune suppression increases the incidence of invasive fungal infections, particularly those caused by the opportunistic mold Aspergillus fumigatus. Previous investigations revealed that members of the Toll-like receptor (TLR) family are not absolutely required for host defense against A. fumigatus in non-immunosuppressed hosts, suggesting that other pattern recognition receptors (PRRs) are involved. We show here that naive mice (i.e. not pharmacologically immunosuppressed) lacking the beta-glucan receptor Dectin-1 (Dectin-1−/−) are more sensitive to intratracheal challenge with A. fumigatus than control mice, exhibiting >80% mortality within 5 days, ultimately attributed to a compromise in respiratory mechanics. In response to A. fumigatus challenge, Dectin-1−/− mice demonstrated impaired interleukin (IL)-α, IL-1β, tumor necrosis factor (TNF)-α, CCL3/macrophage inflammatory protein (MIP)-α, CCL4/MIP-1β and CXCL1/KC production, which resulted in insufficient lung neutrophil recruitment and uncontrolled A. fumigatus lung growth. Alveolar macrophages from Dectin-1−/− mice failed to produce proinflammatory mediators in response to A. fumigatus, whereas neutrophils from Dectin-1−/− mice had impaired reactive oxygen species production and impaired killing of A. fumigatus. We further show that IL-17 production in the lung after A. fumigatus challenge was Dectin-1 dependent and that neutralization of IL-17 significantly impaired A. fumigatus clearance. Collectively, these results support a requisite role for Dectin-1 in in vivo defense against A. fumigatus.
doi:10.4049/jimmunol.0804250
PMCID: PMC3434356  PMID: 19342673
11.  Feasibility of exercising adults with asthma: a randomized pilot study 
Background
Aerobic exercise appears to have clinical benefits for many asthmatics, yet a complete understanding of the mechanisms underlying these benefits has not been elucidated at this time.
Purpose
The objective of this study was to determine feasibility for a larger, future study that will define the effect of aerobic exercise on cellular, molecular, and functional measures in adults with mild-moderate asthma.
Design
Recruited subjects were randomized into usual care (sedentary) or usual care with moderate intensity aerobic exercise treatment groups.
Setting / Participants
Nineteen adults with mild-moderate asthma but without a recent history of exercise were recruited at the UAB Lung Health Center, Birmingham, AL.
Intervention
The exercise group underwent a 12 week walking program exercising at 60 – 75% of maximum heart rate (HRmax). Subjects self-monitored HRmax levels using heart rate monitors; exercise diaries and recreation center sign-in logs were also used.
Main outcome measures
Functional measures, including lung function and asthma control scores, were evaluated for all subjects at pre- and post-study time-points; fitness measures were also assessed for subjects in the exercise group. Peripheral blood and nasal lavage fluid were collected from all subjects at pre- and post-study visits in order to evaluate cellular and molecular measures, including cell differentials and eosinophilic cationic protein (ECP).
Results
Sixteen subjects completed the prescribed protocol. Results show that subjects randomized to the exercise group adhered well (80%) to the exercise prescription and exhibited a trend toward improved fitness levels upon study completion. Both groups exhibited improvements in ACQ scores. No changes were observed in lung function (FEV1, FEV1/FVC), cell differentials, or ECP between groups.
Conclusions
Results indicate that a moderate intensity aerobic exercise training program may improve asthma control and fitness levels without causing asthma deterioration in adult asthmatics. As such, these findings demonstrate the feasibility of the study protocol in preparation for a larger, clinical trial that will elucidate the functional consequences of aerobic exercise on asthmatic cellular and molecular responses.
doi:10.1186/1710-1492-8-13
PMCID: PMC3511803  PMID: 22863207
12.  Postexposure Administration of a β2-Agonist Decreases Chlorine-Induced Airway Hyperreactivity in Mice 
Exposure to chlorine (Cl2) damages airway and alveolar epithelia, resulting in acute lung injury and reactive airway dysfunction syndrome. We evaluated the efficacy and mechanisms by which arformoterol, a long-term β2-agonist, administered after exposure, mitigated the extent of this injury. Exposure of C57BL/6 mice to 400 ppm Cl2 for 30 minutes increased respiratory system resistance and airway responsiveness to aerosolized methacholine (assessed by FlexiVent) up to 6 days after exposure, and decreased Na+-dependent alveolar fluid clearance (AFC). Inducible Nitric Oxide Synthase (iNOS) knockout mice developed similar degrees of airway hyperreactivity as wild-type controls after Cl2 exposure, indicating that reactive intermediates from iNOS do not contribute to Cl2-induced airway dysfunction in our model. Intranasal administration of arformoterol mitigated the Cl2 effects on airway reactivity and AFC, presumably by increasing lung cyclic AMP level. Arformoterol did not modify the inflammatory responses, as evidenced by the number of inflammatory cells and concentrations of IL-6 and TNF-α in the bronchoalveolar lavage. NF-κB activity (assessed by p65 Western blots and electrophoretic mobility shift assay) remained at control levels up to 24 hours after Cl2 exposure. Our results provide mechanistic insight into the effectiveness of long-term β2-agonists in reversing Cl2-induced reactive airway dysfunction syndrome and injury to distal lung epithelial cells.
doi:10.1165/rcmb.2010-0226OC
PMCID: PMC3145072  PMID: 20855648
alveolar fluid clearance; cAMP; iNOS; NF-κB; lung injury
13.  CD40 Ligation Decreases its Protein Half-Life at the Cell Surface 
European journal of immunology  2008;38(3):864-869.
Summary
CD40 is expressed on a variety of tumors; anti-CD40 agonists promote tumor cell apoptosis and subsequent tumor regression. Because the effectiveness of anti-CD40-agonists is dependent upon CD40 surface expression, the current study examined ligation-mediated changes in CD40 protein half-life (t1/2)at the cell surface. This study utilized a CD40+ epithelial cell line (9HTEo-), a CD40 null epithelial cell line (HT-29) engineered to express either wild-type (WT) or mutant (T254A, Q263A, E235A, Δ201) CD40, and the anti-CD40 antibody G28.5. Ligation of endogenous CD40 expressed on 9HTEo-cells decreased CD40 surface protein t1/2 from 13h to 4h (p<0.05). Ligation of WT-, Q263A-, or T254A-CD40 expressed on engineered HT-29 cells decreased CD40 surface protein t1/2 from an average of 8h to 4h (p<0.05); T254A and Q263A contain mutated TRAF2/3 binding sites. In contrast, ligation of E235A andΔ201-CD40 had no affect on its surface protein t1/2 (p<0.05); E235A contains a mutated TRAF6 binding site while Δ201 lacks an intact cytoplasmic tail. These results suggest that anti-CD40 agonists decrease CD40 surface protein t1/2 via a mechanism that involves TRAF6 but not TRAF2/3; the therapeutic implications for CD40-mediated tumor regression are discussed.
doi:10.1002/eji.200737828
PMCID: PMC2915443  PMID: 18253927
CD40; epithelial cell; TRAF molecules
14.  RU486 blocks the anti-inflammatory effects of exercise in a murine model of allergen-induced pulmonary inflammation 
Brain, behavior, and immunity  2005;19(5):413-422.
In an ovalbumin (OVA)-driven murine model of allergic pulmonary inflammation, we have shown previously that moderate-intensity aerobic exercise training attenuates inflammatory responses, disease progression, and NF-κB activation within the sensitized lung. Glucocorticoids (GCs), potent anti-inflammatory agents, have been shown to alter transcriptional events that are important in asthmatic pathogenesis, such as NF-κB activation. Notably, exercise training can alter the production and signaling capacity of endogenous GCs. Because GCs exert their anti-inflammatory effects through binding to intracellular glucocorticoid receptors (GRs), we examined the role of the GR in facilitating the anti-inflammatory effects of exercise. Results show that, in exercised OVA-sensitized mice, treatment with the GR antagonist RU486 blocked the exercise-induced reductions in cellular infiltration of the airways (p < .05), KC and soluble VCAM-1 protein levels in the bronchoalveloar lavage fluid (p < .05), and NF-κB translocation and DNA binding within the lung to levels similar to those observed in sedentary OVA-sensitized mice. Importantly, RU486 treatment also blocked exercise-induced increases in GR nuclear translocation to the levels seen in sensitized control mice. Together, these results suggest that GR nuclear translocation and NF-κ activation play roles in mediating the anti-inflammatory effects of exercise in allergen-mediated lung pathology.
doi:10.1016/j.bbi.2005.04.004
PMCID: PMC2891236  PMID: 15922554
Exercise; Asthma; Inflammation; Glucocorticoids; RU486; NF-κB
15.  Plasma Membrane CFTR Regulates RANTES Expression via Its C-Terminal PDZ-Interacting Motif 
Molecular and Cellular Biology  2003;23(2):594-606.
Despite the identification of 1,000 mutations in the cystic fibrosis gene product CFTR, there remains discordance between CFTR genotype and lung disease phenotype. The study of CFTR, therefore, has expanded beyond its chloride channel activity into other possible functions, such as its role as a regulator of gene expression. Findings indicate that CFTR plays a role in the expression of RANTES in airway epithelia. RANTES is a chemokine that has been implicated in the regulation of mucosal immunity and the pathogenesis of airway inflammatory diseases. Results demonstrate that CFTR triggers RANTES expression via a mechanism that is independent of CFTR's chloride channel activity. Neither pharmacological inhibition of CFTR nor activation of alternative chloride channels, including hClC-2, modulated RANTES expression. Through the use of CFTR disease-associated and truncation mutants, experiments suggest that CFTR-mediated transcription factor activation and RANTES expression require (i) insertion of CFTR into the plasma membrane and (ii) an intact CFTR C-terminal PDZ-interacting domain. Expression of constructs encoding wild-type or dominant-negative forms of the PDZ-binding protein EBP50 suggests that EBP50 may be involved in CFTR-dependent RANTES expression. Together, these data suggest that CFTR modulates gene expression in airway epithelial cells while located in a macromolecular signaling complex at the plasma membrane.
doi:10.1128/MCB.23.2.594-606.2003
PMCID: PMC151526  PMID: 12509457
16.  Epithelial P2X purinergic receptor channel expression and function 
Journal of Clinical Investigation  1999;104(7):875-884.
P2X purinergic receptor (P2XR) channels bind ATP and mediate Ca2+ influx — 2 signals that stimulate secretory Cl– transport across epithelia. We tested the hypotheses that P2XR channels are expressed by epithelia and that P2XRs transduce extracellular ATP signals into stimulation of Cl– transport across epithelia. Electrophysiological data and mRNA analysis of human and mouse pulmonary epithelia and other epithelial cells indicate that multiple P2XRs are broadly expressed in these tissues and that they are active on both apical and basolateral surfaces. Because P2X-selective agonists bind multiple P2XR subtypes, and because P2X agonists stimulate Cl– transport across nasal mucosa of cystic fibrosis (CF) patients as well as across non-CF nasal mucosa, P2XRs may provide novel targets for extracellular nucleotide therapy of CF.
PMCID: PMC408558  PMID: 10510328

Results 1-16 (16)