The innate immune response of large and small airway epithelium to respiratory pathogens in chronic obstructive pulmonary disease

PhD ThesisChronic obstructive pulmonary disease (COPD) is a smoking‐related inflammatory lung disease in which small airways remodelling contributes to loss of lung function. Bacterial colonisation in clinically stable COPD patients may play a role in persisting inflammation despite smoking cessation. I propose that the innate immune response from small airway epithelium is more potent than from large airway epithelium, an effect which may be dampened by cigarette smoke, favouring persistent bacterial colonisation in COPD. Nineteen patients with COPD and eleven healthy volunteers were recruited for investigation. Bronchoalveolar lavage (BAL) differential cell counts and cytokine levels were analysed. Standard BAL culture and culture‐independent bacterial DNA analysis were performed. Submerged cultures of epithelial cells from large (LAEC) and small (SAEC) airway were established. Pro‐inflammatory cytokine release in response to cigarette smoke extract (CSE) and non‐typeable Haemophilus influenzae whole cell lysate (HI) was investigated. Increased neutrophil % and cytokine levels (IL‐8, IL‐6, IL‐1β) were detected in COPD BAL samples compared to controls. Culture‐independent microbiological assessment demonstrated bacterial DNA in BAL samples from both COPD patients and controls: the diversity of bacterial species identified was significantly less in COPD samples. Primary airway epithelial cell cultures were successfully established from 16 COPD patients and 10 healthy controls. LAEC and SAEC from COPD patients and controls demonstrated an increase in IL‐8 release in response to combined CSE (5%) and HI. This effect was greater in SAEC, but no significant difference was observed between disease and control cell responses. The same pattern was observed for IL‐6 release. Corticosteroid pre‐treatment (1nM Dexamethasone or 17‐Beclomethasone monopropionate) did not suppress the cellular responses observed. Differences in large and small airway innate immune responses may be important in COPD pathogenesis. This is important to consider in modelling the disease in‐vitro and in the development of new therapeutic targets.Wellcome Trus