Acute exacerbations are an important contributor to the health care costs, quality of life, morbidity, and mortality of patients with chronic obstructive pulmonary disease (COPD). Airway bacterial infection may promote increased airway inflammation and lead to decreased airway function, and nontypable Haemophilus influenzae is the bacterial species most commonly isolated during COPD exacerbations. H. influenzae strains isolated from COPD patients during acute exacerbations induce more inflammation in a mouse airway infection, induce higher levels of interleukin-8 after interaction with human airway epithelial cells, and adhere more to epithelial cells compared to colonizing strains. Based on these observations, we hypothesize that specific H. influenzae surface molecules control airway epithelial cell interactions with bacteria that determine bacterial capacity to induce high levels of airway inflammation and COPD exacerbations. A better understanding of interactions between H. influenzae and epithelial cells that lead to airway inflammation may uncover strategies for selectively modifying damaging bacterial effects but not beneficial immunity in airway epithelium in patients with COPD. Accordingly, our specific aims are to: I. Compare the airway epithelial cell response to H. influenzae associated with COPD exacerbation versus colonization. We propose that H. influenzae associated with COPD exacerbations induce more inflammation compared to colonizing strains. To investigate this aim, we will take advantage of airway epithelial cell models (including primary cultures of human tracheobronchial epithelial cells) and their sensitivity to interaction with H. influenzae. Comparison of bacterial strains will be accomplished using assays of bacterial adherence and epithelial cell signal transduction pathways and gene expression. II. Determine epithelial cell mechanisms that detect and respond to H. influenzae associated with COPD exacerbations. We propose that specific molecules on the epithelial cell surface detect H. influenzae and activate specific signaling pathways leading to gene expression. To investigate this aim, we will take advantage of the same airway epithelial cell model systems for H. influenzae infection and epithelial cell responses. Critical molecules and pathways important in airway defense will be determined by detecting activation and using specific inhibitory strategies such as dominant-negative molecule expression. III. Identify bacterial factors that regulate the airway epithelial cell response to H. influenzae associated with COPD exacerbations. We propose that specific bacterial molecules interact with and/or are detected by epithelial cells, and that these molecules differ between strains of H. influenzae associated with exacerbation versus colonization. To investigate this aim, we will take advantage of multiple systems that differentiate the expression and function of specific bacterial virulence factors. Expression of important bacterial factors will be identified and linked to epithelial cell adherence and responses.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL082505-01
Application #
7008423
Study Section
Special Emphasis Panel (ZHL1-CSR-A (S1))
Program Officer
Croxton, Thomas
Project Start
2005-09-15
Project End
2010-07-31
Budget Start
2005-09-15
Budget End
2006-07-31
Support Year
1
Fiscal Year
2005
Total Cost
$331,875
Indirect Cost
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Manzel, Lori J; Shi, Lei; O'Shaughnessy, Patrick T et al. (2011) Inhibition by cigarette smoke of nuclear factor-?B-dependent response to bacteria in the airway. Am J Respir Cell Mol Biol 44:155-65
Modestou, Modestos A; Manzel, Lori J; El-Mahdy, Sherif et al. (2010) Inhibition of IFN-gamma-dependent antiviral airway epithelial defense by cigarette smoke. Respir Res 11:64
Manzel, Lori J; Chin, Cecilia L; Behlke, Mark A et al. (2009) Regulation of bacteria-induced intercellular adhesion molecule-1 by CCAAT/enhancer binding proteins. Am J Respir Cell Mol Biol 40:200-10
Winder, Audra A; Wohlford-Lenane, Christine; Scheetz, Todd E et al. (2009) Differential effects of cytokines and corticosteroids on toll-like receptor 2 expression and activity in human airway epithelia. Respir Res 10:96
Cholon, Deborah M; Cutter, David; Richardson, Stephen K et al. (2008) Serial isolates of persistent Haemophilus influenzae in patients with chronic obstructive pulmonary disease express diminishing quantities of the HMW1 and HMW2 adhesins. Infect Immun 76:4463-8
Look, Dwight C; Chin, Cecilia L; Manzel, Lori J et al. (2006) Modulation of airway inflammation by Haemophilus influenzae isolates associated with chronic obstructive pulmonary disease exacerbation. Proc Am Thorac Soc 3:482-3