ABSTRACT
Nontypeable Haemophilus influenzae (NTHi) is the etiological agent most frequently associated with bacterial exacerbations of chronic obstructive pulmonary disease (COPD). The present work shows that NTHi strains induced in primary normal human bronchial epithelial cells (NHBE) a cytokine/chemokine response in which CCL-5 and CXCL-10 were predominant. Production of both cytokines was inhibited by an anti-TLR3 monoclonal antibody (mAb) in a dose-dependent manner, but not by control human IgG4 antibodies, thus suggesting a TLR3-dependency of the NTHi stimulation. BEAS-2B, an immortalized human bronchial epithelial cell line, also showed a similar NTHi-induced response that was inhibited by the anti-TLR3 mAb. A BEAS-2B cell line stably expressing TLR3 siRNA showed significantly reduced cytokine/chemokine responses to NTHi stimulation, confirming the role of TLR3 in the response. These results indicate that TLR3 is a key component in the response of human bronchial epithelial cells to NTHi, and suggest that cognate neutralizing mAbs might be a useful therapeutic tool to regulate the inflammatory response.
Subject(s)
Bronchi/cytology , Epithelial Cells/microbiology , Haemophilus influenzae/physiology , Toll-Like Receptor 3/metabolism , Antibodies, Monoclonal/pharmacology , Cell Line , Cells, Cultured , Chemokine CCL5/metabolism , Chemokine CXCL10/metabolism , Chemokines/metabolism , Cytokines/metabolism , Dose-Response Relationship, Drug , Epithelial Cells/cytology , Epithelial Cells/metabolism , Host-Pathogen Interactions , Humans , RNA Interference , Toll-Like Receptor 3/genetics , Toll-Like Receptor 3/immunologyABSTRACT
The combination of ketamine and propofol for procedural sedation and analgesia theoretically may be beneficial, with the rationale being that using lower doses of each agent may result in a reduction of the undesirable adverse effects of both agents while maintaining optimal conditions for performing procedures. To examine the current evidence for the efficacy and safety of ketamine and propofol in combination for procedural sedation and analgesia, we searched the MEDLINE (1966-March 2007), EMBASE (1980-March 2007), and Cochrane Database of Systematic Reviews (through the first quarter of 2007) databases for reports describing the use of ketamine and propofol in combination for procedural sedation and analgesia. Additional published reports were identified through a manual search of references from retrieved articles. Prospective, comparative, full-text reports of studies performed in humans that were published in English were reviewed for inclusion. Both authors independently evaluated all studies. Studies in adult and pediatric patients were included if they evaluated efficacy or safety end points. Eight clinical trials were included, seven of which compared a combination of propofol and ketamine with propofol monotherapy. In these trials, variable milligram:milligram ratios of propofol and ketamine were used, ranging from 10:1-2:1, and the optimum dose of these agents in combination is unclear. Combination propofol and ketamine has not demonstrated superior clinical efficacy compared with propofol alone for procedural sedation and analgesia. Conflicting data exist regarding reduced hemodynamic and respiratory complications in patients receiving the combination compared with propofol monotherapy. At higher doses, the addition of ketamine to propofol may incur more adverse effects. Compatibility data for the two agents combined in a syringe are limited. The available evidence does not support the use of a fixed-dose ketamine-propofol combination for procedural sedation and analgesia. Further research is needed to elucidate the role, if any, of this combination for procedural sedation and analgesia.
