Abbreviations: ALI = air-liquid interface; AP = apical; BL = basolateral; CCK-8 = cell counting kit-8; CF = cystic fibrosis; DEX = dexamethasone; DMSO = dimethylsulfoxide; DPB = diffuse panbronchiolitis; ERK = extracellular-regulated protein kinase; ETT = endotrachial tube; GAPDH = glyceraldehyde-3-phosphate dehydrogenase; HRP = horseradish peroxidase; JNK = c-Jun NH2– terminal protein kinase; LPS = Lipopolysaccharide; MAPK = mitogen-activated protein kinase; MCT = mucociliary transport; MEK = mitogen-activated protein kinase/extracellular-regulated protein kinase kinase; NF-kB = nuclear factor-кВ; NHBE = normal human bronchial epithelial; PD98059 = 2′-amino-3′-methoxyflavone; SAPK = stress-activated protein kinase; TLR4 = toll-like receptor 4.
In response to bacterial invasion, mucociliary clearance is stimulated, and inflammatory mediators and cytokines are secreted as a defense, but these also can damage the airway. Among epithelial-derived pleiotropic cytokines, IL-8, a member of the cysteine-X-cysteine chemokine family, acts as one of the most potent neutrophil chemoattractants. Neutrophil-dominated inflammation is a characteristic of COPD, diffuse panbronchiolitis (DPB), and cystic fibrosis (CF). IL-8 is produced by airway epithelial cells. Increased IL-8 in sputum and BAL fluid is associated with the severity of DPB and CF,- and there is increased IL-8 gene expression in the bronchial epithelium of subjects with severe asthma and COPD.
Proinflammatory cytokines, bacterial flagellin, and lipopolysaccharide (LPS) can increase IL-8 production by normal human bronchial epithelial (NHBE) cells. Among the many agents present in organic dusts, LPS is a major inducer of the inflammatory reaction.10 LPS binds to toll-like receptor 4 (TLR4), which activates intracellular signaling pathways, including the nuclear factor-kB (NK-kB) pathway, phosphatidylinositol 3 kinase, and mitogen-activated protein kinase (MAPK) pathways. Three MAPK pathways contribute to IL-8 gene expression: the extracellular-regulated protein kinase (ERK), c-Jun NH2-terminal protein kinase (JNK), and p38 MAPK cascades. The relative degree of activation of each pathway and the functional consequences differ among cell types and experimental systems.