Bhattacharya M.,University of California at San Francisco |
Sundaram A.,University of California at San Francisco |
Kudo M.,Yokohama City University |
Farmer J.,University of California at San Francisco |
And 7 more authors.
Journal of Clinical Investigation | Year: 2014
The intracellular scaffold protein IQGAP1 supports protein complexes in conjunction with numerous binding partners involved in multiple cellular processes. Here, we determined that IQGAP1 modulates airway smooth muscle contractility. Compared with WT controls, at baseline as well as after immune sensitization and challenge, Iqgap1-/- mice had higher airway responsiveness. Tracheal rings from Iqgap1-/- mice generated greater agonist-induced contractile force, even after removal of the epithelium. RhoA, a regulator of airway smooth muscle contractility, was activated in airway smooth muscle lysates from Iqgap1-/- mice. Likewise, knockdown of IQGAP1 in primary human airway smooth muscle cells increased RhoA activity. Immunoprecipitation studies indicated that IQGAP1 binds to both RhoA and p190A-RhoGAP, a GTPase-activating protein that normally inhibits RhoA activation. Proximity ligation assays in primary airway human smooth muscle cells and mouse tracheal sections revealed colocalization of p190A-RhoGAP and RhoA; however, these proteins did not colocalize in IQGAP1 knockdown cells or in Iqgap1-/- trachea. Compared with healthy controls, human subjects with asthma had decreased IQGAP1 expression in airway biopsies. Together, these data demonstrate that IQGAP1 acts as a scaffold that colocalizes p190ARhoGAP and RhoA, inactivating RhoA and suppressing airway smooth muscle contraction. Furthermore, our results suggest that IQGAP1 has the potential to modulate airway contraction severity in acute asthma.
Ilarraza R.,Pulmonary Research Group |
Wu Y.,Pulmonary Research Group |
Adamko D.J.,Pulmonary Research Group |
Adamko D.J.,University of Alberta |
Adamko D.J.,University of Saskatchewan
International Archives of Allergy and Immunology | Year: 2012
Background: Leukotrienes are potent inflammatory mediators which modulate immune responses and induce bronchoconstriction in susceptible individuals. Montelukast (MK) is a leukotriene receptor (CysLT1) antagonist that has been shown to prevent exacerbation of asthma. Considering the plethora of potential cellular targets for MK, specific mechanisms for its therapeutic action are still not fully understood. In vitro, we determined whether human dendritic cell function could be affected by leukotriene C4 (LTC4) treatment and whether MK had potential in modulating this response. We also studied the effect of LTC4 in the context of response to an airway virus (respiratory syncytial virus, RSV). Methods: Human monocyte-derived dendritic cells (moDCs) exposed to LTC4, MK, or both, were cocultured with autologous T cells, with or without RSV. The effects of LTC4 and MK on cell function were determined by ELISA and proliferation assays. Results: Both moDCs and their precursors - monocytes - express LTC4 receptor CysLT1, making them potential targets for MK. moDCs cultured with LTC4 release the eosinophil chemoattractant RANTES (CCL5) and induce greater T cell proliferation. Both were blocked by the presence of MK. MK treatment, albeit anti-inflammatory, did not interfere with the moDC-dependent T cell-proliferative responses induced by RSV. Conclusions: LTC4, chronically present in the airways of asthma patients, could induce an exaggerated inflammatory response to airway infection via dendritic cell activation, which would be prevented by MK. Our study provides additional insight into the mechanisms of action of this leukotriene receptor antagonist. Copyright © 2012 S. Karger AG, Basel.
Koeverden I.V.,Radboud University Nijmegen |
Koeverden I.V.,Pulmonary Research Group |
Blanc P.D.,University of California at San Francisco |
Bowler R.P.,National Jewish Health |
And 2 more authors.
COPD: Journal of Chronic Obstructive Pulmonary Disease | Year: 2015
Background: Exposure to secondhand tobacco smoke (SHS) can be a risk factor for chronic obstructive pulmonary disease (COPD), but its role among relatively heavy smokers with potential co-exposure to workplace vapors, gas, dust, and fumes (VGDF) has not been studied. Methods: To estimate the contribution of SHS exposure to COPD risk, taking into account smoking effects and work-related exposures to VGDF, we quantified SHS based on survey responses for 1400 ever-employed subjects enrolled in the COPDGene study, all current or former smokers with or without COPD. Occupational exposures to VGDF were quantified based on a job exposure matrix. The associations between SHS and COPD were tested in multivariate logistic regression analyses adjusted for age, sex, VGDF exposure, and cumulative smoking. Results and Discussion: Exposures to SHS at work and at home during adulthood were associated with increased COPD risk: odds ratio (OR) = 1.12 (95% confidence interval CI: 1.02-1.23; p = 0.01) and OR = 1.09 (95%CI: 1.00-1.18; p = 0.04) per 10 years of exposure adjusted for smoking and other covariates, respectively. In addition, subjects with employment histories likely to entail exposure to VGDF were more likely to have COPD: OR = 1.52 (95%CI: 1.16-1.98; p < 0.01) (adjusted for other covariates). While adult home SHS COPD risk was attenuated among the heaviest smokers within the cohort, workplace SHS and job VGDF risks persisted in that stratum. Conclusion: Among smokers all with at least 10 pack-years, adult home and work SHS exposures and occupational VGDF exposure are all associated with COPD. © 2015 Informa Healthcare USA, Inc.
Donde A.,University of California at San Francisco |
Wong H.,University of California at San Francisco |
Frelinger J.,University of California at San Francisco |
Frelinger J.,Pulmonary Research Group |
And 5 more authors.
Journal of Occupational and Environmental Medicine | Year: 2012
BACKGROUND: Intermittent moderate-intensity exercise is used in human inhalational exposure studies to increase the effective dose of air pollutants. OBJECTIVE: To investigate the inflammatory, coagulatory, and autonomic effects of intermittent moderate-intensity exercise. METHODS: We measured hemodynamic, electrocardiographic, inflammatory, and coagulatory parameters in peripheral blood of 25 healthy subjects across an exercise protocol that included running on a treadmill or pedaling a cycle ergometer for 30 minutes every hour over 4 hours in a climate-controlled chamber with a target ventilation of 20 L/min/m body surface area. RESULTS: Intermittent moderate-intensity exercise induced a systemic proinflammatory response characterized by increases in leukocyte counts, C-reactive protein, monocyte chemoattractant protein-1, and interleukin-6, but did not change coagulation tendency or heart rate variability. CONCLUSION: Interpretation of pollutant-induced inflammatory responses in inhalational exposure studies should account for signals and noises caused by exercise, especially when the effect size is small. © 2012 The American College of Occupational and Environmental Medicine.
Arjomandi M.,San Francisco General Hospital |
Arjomandi M.,University of California at San Francisco |
Arjomandi M.,Pulmonary Research Group |
Wong H.,San Francisco General Hospital |
And 10 more authors.
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2015
Epidemiological evidence suggests that exposure to ozone increases cardiovascular morbidity. However, the specific biological mechanisms mediating ozone-associated cardiovascular effects are unknown. To determine whether short-term exposure to ambient levels of ozone causes changes in biomarkers of cardiovascular disease including heart rate variability (HRV), systemic inflammation, and coagulability, 26 subjects were exposed to 0, 100, and 200 ppb ozone in random order for 4 h with intermittent exercise. HRV was measured and blood samples were obtained immediately before (0 h), immediately after (4 h), and 20 h after (24 h) each exposure. Bronchoscopy with bron-choalveolar lavage (BAL) was performed 20 h after exposure. Regression modeling was used to examine dose-response trends between the endpoints and ozone exposure. Inhalation of ozone induced dose-dependent adverse changes in the frequency domains of HRV across exposures consistent with increased sympathetic tone [increase of (parameter estimate ± SE) 0.4 ± 0.2 and 0.3 ± 0.1 in low- to high-frequency domain HRV ratio per 100 ppb increase in ozone at 4 h and 24 h, respectively (P = 0.02 and P = 0.01)] and a dose-dependent increase in serum C-reactive protein (CRP) across exposures at 24 h [increase of 0.61 ± 0.24 mg/l in CRP per 100 ppb increase in ozone (P = 0.01)]. Changes in HRV and CRP did not correlate with ozone-induced local lung inflammatory responses (BAL granulocytes, IL-6, or IL-8), but changes in HRV and CRP were associated with each other after adjustment for age and ozone level. Inhalation of ozone causes adverse systemic inflammatory and cardiac autonomic effects that may contribute to the cardiovascular mortality associated with short-term exposure. © 2015 American Physiological Society. All Rights Reseved.