RESUMO
BACKGROUND: Heightened inflammation, including expression of COX-2, is associated with COPD pathogenesis. RelB is an NF-κB family member that attenuates COX-2 in response to cigarette smoke by a mechanism that may involve the miRNA miR-146a. There is no information on the expression of RelB in COPD or if RelB prevents COX-2 expression through miR-146a. METHODS: RelB, Cox-2 and miR-146a levels were evaluated in lung fibroblasts and blood samples derived from non-smokers (Normal) and smokers (At Risk) with and without COPD by qRT-PCR. RelB and COX-2 protein levels were evaluated by western blot. Human lung fibroblasts from Normal subjects and smokers with and without COPD, along with RelB knock-down (siRNA) in Normal cells, were exposed to cigarette smoke extract (CSE) in vitro and COX-2 mRNA/protein and miR-146a levels assessed. RESULTS: Basal expression of RelB mRNA and protein were significantly lower in lung cells derived from smokers with and without COPD, the latter of which expressed more Cox-2 mRNA and protein in response to CSE. Knock-down of RelB in Normal fibroblasts increased Cox-2 mRNA and protein induction by CSE. Basal miR-146a levels were not different between the three groups, and only Normal fibroblasts increased miR-146a expression in response to smoke. There was a positive correlation between systemic RelB and Cox-2 mRNA levels and circulating miR-146a levels were higher only in GOLD stage I subjects. CONCLUSIONS: Our data indicate that RelB attenuates COX-2 expression in lung structural cells, such that loss of pulmonary RelB may be an important determinant in the aberrant, heightened inflammation associated with COPD pathogenesis.
Assuntos
Ciclo-Oxigenase 2/biossíntese , Fibroblastos/metabolismo , Pulmão/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Fumar/metabolismo , Fator de Transcrição RelB/biossíntese , Idoso , Células Cultivadas , Estudos Transversais , Feminino , Fibroblastos/efeitos dos fármacos , Regulação da Expressão Gênica , Humanos , Pulmão/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , NF-kappa B/biossíntese , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Fumaça/efeitos adversos , Fumar/epidemiologia , Nicotiana/toxicidadeRESUMO
BACKGROUND AND OBJECTIVE: We investigated the effect of nonsteroidal anti-inflammatory drug (NSAID) use on stage of colon cancer and presence of distant metastases at diagnosis. METHODS: Cases of incident colon cancer diagnosed between 1981 and mid-1995 were selected from the Saskatchewan Cancer Registry. Cases with more extensive cancer at diagnosis were compared with cases with less extensive cancer (characterized using the Dukes system). NSAID exposure was assessed using the Saskatchewan Prescription Drug Plan database. RESULTS: Compared with non-users in the same period, nonmetastatic cancer was found to be less extensive in those with low NSAID use (odds ratio [OR] 0.67, 95% confidence interval [CI] 0.53-0.87) and high NSAID use (OR 0.55, 95%CI 0.36-0.84) during the 6 to 10 year periods preceding diagnosis, regardless of the cut-off used to define "more extensive cancer." NSAID use in the 2 to 5 year periods was also found to protect (although not statistically significantly) against the occurrence of distant metastasis. CONCLUSION: Results are consistent with the hypothesized mechanism of the action of NSAIDs, but confounding by healthy lifestyle cannot be ruled out.