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Upregulation of intercellular adhesion molecule-1 (ICAM-1) is frequently implicated in lung inflammation. Lipopolysaccharide (LPS) has been shown to play a key role in inflammation via adhesion molecule induction and then causes lung injury. However, the mechanisms underlying LPS-induced ICAM-1 expression in human pulmonary alveolar epithelial cells (HPAEpiCs) remain unclear. We showed that LPS induced ICAM-1 expression in HPAEpiCs, revealed by Western blotting, RT-PCR, real-time PCR, and promoter assay. Pretreatment with the inhibitor of c-Src (protein phosphatase-1, PP1), reactive oxygen species (ROS) (Edaravone), NADPH oxidase (apocynin and diphenyleneiodonium chloride), EGFR (AG1478), PDGFR (AG1296), phosphatidylinositol-3-kinase (PI3K) (LY294002), MEK1/2 (U0126), or NF-κB (Bay11-7082) and transfection with siRNAs of c-Src, EGFR, PDGFR, Akt, p47phox, Nox2, Nox4, p42, and p65 markedly reduced LPS-induced ICAM-1 expression and monocyte adherence to HPAEpiCs challenged with LPS. In addition, we established that LPS stimulated phosphorylation of c-Src, EGFR, PDGFR, Akt, or p65, which was inhibited by pretreatment with their respective inhibitors. LPS induced Toll-like receptor 4 (TLR4), MyD88, TNF receptor-associated factor 6 (TRAF6), c-Src, p47phox, and Rac1 complex formation 2, which was attenuated by transfection with c-Src or TRAF6 siRNA. Furthermore, LPS markedly enhanced NADPH oxidase activation and intracellular ROS generation, which were inhibited by PP1. We established that LPS induced p42/p44 MAPK activation via a c-Src/NADPH oxidase/ ROS/EGFR, PDGFR/PI3K/Akt-dependent pathway in these cells. Finally, we observed that LPS significantly enhanced NF-κB and IκBα phosphorylation, NF-κB translocation, and NF-κB promoter activity, which were inhibited by PP1, Edaravone, apocynin, diphenyleneiodonium chloride, AG1478, AG1296, LY294002, or U0126. These results demonstrated that LPS induces p42/p44 MAPK activation mediated through the TLR4/MyD88/TRAF6/c-Src/NADPH oxidase/ ROS/EGFR, PDGFR/PI3K/Akt pathway, which in turn initiates the activation of NF-κB and ultimately induces ICAM-1 expression in HPAEpiCs. lipopolysaccharide [ABSTRACT FROM AUTHOR]

Staphylococcus aureus is the most commonly found Gram-positive bacterium in patients admitted to intensive-care units, causing septicaemia or pneumonia. S. aureus is considered to play an important role in the induction of cell adhesion molecules. Resveratrol, a compound found in the skins of red fruits, may inhibit the inflammatory signalling pathways involved in lung diseases. In the present paper, we have shown that resveratrol reduced S. aureus-mediated VCAM-1 (vascular cell adhesion molecule-1) expression in HPAEpiCs (human lung epithelial cells) and lungs of mice. In an in vivo study, we have shown that resveratrol inhibited S. aureus-induced pulmonary haematoma and leucocyte count in BAL (bronchoalveolar lavage) fluid in mice. In an in vitro study, we observed that resveratrol attenuated S. aureus-induced TLR2 (Toll-like receptor 2), MyD88 (myeloid differentiation factor 88) and PI3K (phosphoinositide 3-kinase) complex formation. S. aureus stimulated Akt, JNK1/2 (c-Jun N-terminal kinase 1/2) and p42/p44 MAPK (mitogen-activated protein kinase) phosphorylation, which were inhibited by resveratrol. In addition, S. aureus induced IκB (inhibitor of nuclear factor κB) a and NF-κB (nuclear factor κB) p65 phosphorylation and NF-κB p65 translocation, which were reduced by resveratrol. Finally, we found that S. aureus induced NF-κB and p300 complex formation and p300 phosphorylation, which were inhibited by resveratrol. Thus resveratrol functions as a suppressor of S. aureus-induced inflammatory signalling not only by inhibiting VCAM-1 expression, but also by reducing TLR2-MyD88-PI3K complex formation and Akt, JNK1/2, p42/p44 MAPK, p300 and NF-κB activation in HPAEpiCs. [ABSTRACT FROM AUTHOR]