| Summary: | 碩士 === 國立中山大學 === 生物科學系研究所 === 102 === Ventilator-associated pneumonia (VAP) is a common nosocomial infection among intensive care unit (ICU) patients and the most common frequent causative microorganism is P. aeruginosa although it rarely causes pneumonia outside the ICU. To study the pathogenesis mechanism of VAP caused by P. aeruginosa colonization, first, C57BL/6 (WT) mice and JNK1 knockout (JNK1-/-) mice received ventilation for 3 hr at 2 days after receiving nasal instillation of P. aeruginosa to induce lung injury. Second, alveolar macrophages (AMs) isolated from WT, JNK1-/- and IKK△mye (deletion of IκB kinase in myeloid cells) mice were ex vivo stimulated with live P. aeruginosa and supernatants were collected for proinflammatory cytokine assay. WT and JNK1-/- mice also received ventilation at 1 hr after receiving nasal instillation of the collected supernatant to induce lung injury. Instillation of P. aeruginosa before ventilation significantly increased the neutrophil sequestration in lungs as well as the levels of pro-inflammatory cytokines and nitrite in bronchoalveolar lavage fluid of WT mice. Instillation of supernatant before ventilation induced more severe lung injury in WT mice and the proinflammatory cytokine assay of supernatant indicated that TNF-α is a critical regulator of VAP induced by P. aeruginosa. Moreover, AMs of IKK△mye mice showed decreased production of TNF-α after ex vivo stimulation but not the AMs of JNK1-/- mice, and instillation of P. aeruginosa before ventilation induced less lung injury in JNK1-/- mice. These results suggest that the pathogenesis mechanism of VAP caused by P. aeruginosa involves production of TNF-α through activation of NF-κB in alveolar macrophages and JNK signaling pathway in lung tissue.
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