Publications

Airway epithelial cancer cells produce increased amounts of the chemokine interleukin-8 (IL-8), inducing pro-tumor responses. Multiple stimuli induce airway epithelial IL-8 production epidermal growth factor receptor (EGFR) dependently, but the mechanisms that exaggerate IL-8 production in airway cancers remain unknown. Here we show that direct activation of EGFR (EGFR-P) by its ligand transforming growth factor (TGF)-alpha induces a second EGFR-P in human airway (NCI-H292) cancer cells but not in normal human bronchial epithelial (NHBE) cells, exaggerating IL-8 production in these cancer cells. The second EGFR-P in NCI-H292 cells was caused by metalloprotease TNF-alpha-converting enzyme (TACE)-dependent cleavage of EGFR pro-ligands and was responsible for most of the total IL-8 induced by TGF-alpha. In NCI-H292 cells, TGF-alpha induced cyclooxygenase (COX)-2-dependent prostaglandin (PG)E2 production and release. PGE2 increased the second EGFR-P and IL-8 production via binding to its Gi-protein-coupled E-prostanoid (EP)3 receptor. In NHBE cells, TGF-alpha-induced EGFR-P did not lead to PGE2 production or to a second EGFR-P, and less IL-8 was produced. Thus, we conclude that a positive feedback pathway involving COX-2/PGE2/EP3 receptor-dependent EGFR reactivation exaggerates IL-8 production in NCI-H292 cancer cells but not in NHBE (normal) cells.

BACKGROUND AND AIMS

This review summarizes the scientific literature relevant to occupational risk factors for chronic obstructive pulmonary disease (COPD).

MATERIAL AND METHODS

This review emphasizes recent work in the field, while placing this in the context of two previous systematic reviews of the subject.

RESULTS

Both the earlier summaries of the literature estimated that the population attributable risk percent (PAR%) of COPD linked to occupational exposures is approximately 15%. More recent studies also strongly support the association between workplace exposures and COPD. Among never smokers, the PAR% for work-related factors may approach 40%. Emerging data also indicate that occupational exposures, at a minimum, are additive to smoking-associated risk of COPD.

CONCLUSIONS

The PAR% for work-related COPD is at least 15%. Scientific significance. The consistency, strength, and plausibility of these data support a causal relationship between occupational exposures and COPD.