RESUMO
The pathogenic bacterium Pseudomonas aeruginosa utilizes the 3-oxododecanoyl homoserine lactone (3OC(12)-HSL) autoinducer as a signaling molecule to coordinate the expression of virulence genes through quorum sensing. 3OC(12)-HSL also affects responses in host cells, including the upregulation of genes encoding inflammatory cytokines. This proinflammatory response may exacerbate underlying disease during P. aeruginosa infections. The specific mechanism(s) through which 3OC(12)-HSL influences host responses is unclear, and no mammalian receptors for 3OC(12)-HSL have been identified to date. Here, we report that 3OC(12)-HSL increases mRNA levels for a common panel of proinflammatory genes in murine fibroblasts and human lung epithelial cells. To identify putative 3OC(12)-HSL receptors, we examined the expression patterns of a panel of nuclear hormone receptors in these two cell lines and determined that both peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) and PPARgamma were expressed. 3OC(12)-HSL functioned as an agonist of PPARbeta/delta transcriptional activity and an antagonist of PPARgamma transcriptional activity and inhibited the DNA binding ability of PPARgamma. The proinflammatory effect of 3OC(12)-HSL in lung epithelial cells was blocked by the PPARgamma agonist rosiglitazone, suggesting that 3OC(12)-HSL and rosiglitazone are mutually antagonistic negative and positive regulators of PPARgamma activity, respectively. These data identify PPARbeta/delta and PPARgamma as putative mammalian 3OC(12)-HSL receptors and suggest that PPARgamma agonists may be employed as anti-inflammatory therapeutics for P. aeruginosa infections.
Assuntos
Homosserina/análogos & derivados , Mediadores da Inflamação/metabolismo , Lactonas/farmacologia , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Pseudomonas aeruginosa/efeitos dos fármacos , Animais , Western Blotting , Linhagem Celular Tumoral , Citocinas/genética , Citocinas/metabolismo , DNA/metabolismo , Ensaio de Desvio de Mobilidade Eletroforética , Homosserina/farmacologia , Humanos , Camundongos , Células NIH 3T3 , PPAR gama/genética , PPAR gama/metabolismo , PPAR beta/genética , PPAR beta/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/antagonistas & inibidores , Receptores Ativados por Proliferador de Peroxissomo/genética , Ligação Proteica/efeitos dos fármacos , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Rosiglitazona , Tiazolidinedionas/farmacologia , Transcrição Gênica/efeitos dos fármacosRESUMO
Mediastinitis is a rare complication of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). Recent reports of infectious complications following EBUS-TBNA involved oropharyngeal bacteria. Here, we report 2 unusual cases of post-EBUS-TBNA mediastinitis involving Streptococcus pneumoniae and Pseudomonas aeruginosa, which were likely the result of direct inoculation of the organisms at the time of transbronchial needle aspiration. The first case was successfully treated with computed tomography-guided drainage and antibiotics, whereas the second case had >50% distal tracheal obstruction and near total occlusion of the left main stem bronchus, requiring rigid bronchoscopy, stent placement, debulking, and antibiotics. Review of literature suggests that the isolated pathogens are rare in this setting and are most likely not related to oropharyngeal contamination during bronchoscope insertion. Active bronchitis should be considered an additional risk factor for EBUS-TBNA-induced mediastinitis. We suggest possible methods to decrease the risk of this serious postprocedure complication. It is important to be vigilant about the possibility of mediastinitis in patients that undergo EBUS-TBNA. Fever and respiratory symptoms should lower the threshold for ordering a computed tomography chest for early detection and management. Our patients did not require thoracic surgery for the management of the mediastinitis.