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Aims: Cigarette smoke is a major risk factor for the development of chronic obstructive pulmonary disease (COPD). The gram negative strain Haemophilus influnenzae (H.i.) plays a major role during exacerbations in patients with COPD. NF-κB plays a central role in inflammatory responses and the innate immune system.
Aim: We will establish a mouse model of COPD that combines the exposure of cigarette smoke (CS) and a bacterial challenge with H.i. Additionally we will investigate the role of NF-κB in CS driven inflammation.
Methods: Mice were exposed to CS in a smoking machine at an average concentration of 120mg/m3 of total suspended particles (TSP) for different time points of 2 weeks up to 6 months at 3 hours per day. After the CS exposure the mice were additionally challenged with nebulized lysate of inactivated H.i. at a concentration of 2.5mg/ml of total protein for 40min. To investigate the role of NF-κB in CS driven inflammation we used mice with deleted p65 in myeloid cells. These animals were CS exposed at an average TSP of 120mg/m3 for 2 weeks up to 6 months. We analyzed the inflammatory response by ELISA, Western-Blot, real-time PCR and immunohistochemistry. To detect structural changes the lungs were prepared by uniform random sampling and analyzed by stereological methods.
Results: The combination of CS and H.i. induced a synergistically higher release of KC and TNFα into the BAL as compared to the controls. CS not only blocked neutrophil influx in BAL but also IL-1β and MIPγ release in lung homogenate after H.i. In contrast CS exposed animals with deleted myeloid p65 showed significantly more TNFα and KC in the BAL and lung homogenates and a higher expression of MMP-9 compared to CS exposed controls.
Conclusion: Our data show that bacterial infections play an important role in animal models of COPD. Myeloid NF-κB plays an anti-inflammatory role in CS induced pulmonary inflammation. This may be an important mechanism in the pathogenesis of COPD.