The role of IRAK4 in an acute cigarette smoke-induced model of pulmonary injury

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Introduction: Chronic obstructive pulmonary disease (COPD) is characterised by persistent inflammation and tissue remodelling and is linked to smoking tobacco. It is thought that the chronic inflammation associated with the disease and pathogen-triggered exacerbation episodes drive the lung damage. Reducing this inflammation could slow the relentless progression of this deadly disease with high clinical unmet need. IRAK4 is thought to be a kinase central to many inflammatory pathways downstream of toll-like receptors (TLRs) and IL-1 family receptors. Hypothesis and aim: We hypothesise that IRAK4 contributes to cigarette smoke (CS) induced lung injury and that depleting or inhibiting it has the potential to ameliorate CS-induced pathophysiology. Methods: Wild type and IRAK4 knock out (KO) mice were exposed to inhaled CS for 50 minutes, twice a day for three days. We assessed levels of neutrophils, cytokines, proteases, lung damage markers (desmosine) and markers of epithelial barrier integrity loss (albumin and plasma SP-D). Results: IRAK4 KO mice appeared to be protected from CS-induced increase in neutrophils, pro-inflammatory cytokines and epithelial membrane damage markers assessed in BAL fluid. These effects were associated with a reduction in proteolytic enzymes (e.g. neutrophil elastase, proteinase 3 and MMP12) which in turn was linked to a lessening of a lung tissue damage marker, desmosine. Discussion: IRAK4 shows potential as a novel therapeutic target for the treatment of COPD by reducing the progression of lung damage and the loss of the epithelial barrier.

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