Fluticasone Induces Epithelial Injury and Alters Barrier Function in Normal Subjects.

OBJECTIVE: The airway epithelium has a number of roles pivotal to the pathogenesis of asthma, including provision of a physical and immune barrier to the inhaled environment. Dysregulated injury and repair responses in asthma result in loss of airway epithelial integrity. Inhaled corticosteroids are a corner stone of asthma treatment. While effective in controlling asthma symptoms, they fail to prevent airway remodeling. Direct cytopathic effects on the airway epithelium may contribute to this. METHODS: This study examined the effects of a 4-week treatment regimen of inhaled fluticasone 500 µg twice daily in healthy human subjects. Induced sputum was collected for cell counts and markers of inflammation. Barrier function was examined by diethylenetriaminepentacetic acid (DTPA) clearance measured by nuclear scintillation scan, and albumin concentration in induced sputum. RESULTS: Steroid exposure resulted in epithelial injury as measured by a significant increase in the number of airway epithelial cells in induced sputum. There was no change in airway inflammation by induced sputum inflammatory cell counts or cytokine levels. Epithelial shedding was associated with an increase in barrier function, as measured by both a decrease in DTPA clearance and decreased albumin in induced sputum. This likely reflects the normal repair response. CONCLUSION: Inhaled corticosteroids cause injury to normal airway epithelium. These effects warrant further evaluation in asthma, where the dysregulated repair response may contribute to airway remodeling.

Community-acquired pneumonia in older patients: does age influence systemic cytokine levels in community-acquired pneumonia?

BACKGROUND AND OBJECTIVE: Community-acquired pneumonia (CAP) is a major cause of death in the elderly. The age-related increase in comorbid illnesses plays a part but the effect of aging on the immune response may be equally important. We aimed to evaluate patients with CAP for evidence of a muted response to infection in elderly patients admitted to hospital compared with a younger patient group. METHODS: Patients with CAP admitted through the Emergency Department were recruited for this prospective observational study. Clinical data were collected at presentation. Severity of pneumonia was assessed using the British Thoracic Society confusion, urea nitrogen, respiratory rate, blood pressure (CURB) score, the Pneumonia Severity Index (PSI) and the systemic inflammatory response syndrome (SIRS) definition. IL-6 and IL-10 levels were measured within 24 h of admission. RESULTS: Eighty patients were included in the study, of whom 38 (48%) were female. The median age was 74 years (range 18-95). Patients greater than 65 years of age had a lower incidence of chest pain and a higher incidence of altered mental status on presentation. CURB score and PSI were higher in the older patients. SIRS showed similar frequencies in both groups. IL-6 and IL-10 levels were similar in young (< 65 years), older (> 65 years) and very elderly (> 80 years) patients. This finding was not altered by severity of pneumonia. CONCLUSIONS: Age does not diminish the severity of illness scores in patients with CAP. There was no blunting of the systemic cytokine response with advanced age in this study.

Epithelial expression of TLR4 is modulated in COPD and by steroids, salmeterol and cigarette smoke.

The toll-like receptors (TLRs) are a key component of host defense in the respiratory epithelium. Cigarette smoking is associated with increased susceptibility to infection, while COPD is characterised by bacterial colonisation and infective exacerbations. We found reduced TLR4 gene expression in the nasal epithelium of smokers compared with non-smoking controls, while TLR2 expression was unchanged. Severe COPD was associated with reduced TLR4 expression compared to less severe disease, with good correlation between nasal and tracheal expression. We went on to examine the effect of potential modulators of TLR4 expression in respiratory epithelium pertinent to airways disease. Using an airway epithelial cell line, we found a dose-dependent downregulation in TLR4 mRNA and protein expression by stimulation with cigarette smoke extracts. Treatment with the corticosteroids fluticasone and dexamethasone resulted in a dose-dependent reduction in TLR4 mRNA and protein. The functional significance of this effect was demonstrated by impaired IL-8 and HBD2 induction in response to LPS. Stimulation with salmeterol (10-6 M) caused upregulation of TLR4 membrane protein presentation with no upregulation of mRNA, suggesting a post-translational effect. The effect of dexamethasone and salmeterol in combination was additive, with downregulation of TLR4 gene expression, and no change in membrane receptor expression. Modulation of TLR4 in respiratory epithelium may have important implications for airway inflammation and infection in response to inhaled pathogens.