Non-essential role for TLR2 and its signaling adaptor Mal/TIRAP in preserving normal lung architecture in mice

Myeloid differentiation factor 88 (MyD88) and MyD88-adaptor like (Mal)/Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) play a critical role in transducing signals downstream of the Toll-like receptor (TLR) family. While genetic ablation of the TLR4/MyD88 signaling axis in mice leads to pulmonary cell death and oxidative stress culminating in emphysema, the involvement of Mal, as well as TLR2 which like TLR4 also signals via MyD88 and Mal, in the pathogenesis of emphysema has not been studied. By employing an in vivo genetic approach, we reveal here that unlike the spontaneous pulmonary emphysema which developed in Tlr42/2 mice by 6 months of age, the lungs of Tlr22/2 mice showed no physiological or morphological signs of emphysema. A more detailed comparative analysis of the lungs from these mice confirmed that elevated oxidative protein carbonylation levels and increased numbers of alveolar cell apoptosis were only detected in Tlr42/2 mice, along with up-regulation of NADPH oxidase 3 (Nox3) mRNA expression. With respect to Mal, the architecture of the lungs of Mal2/2 mice was normal. However, despite normal oxidative protein carbonylation levels in the lungs of emphysema-free Mal2/2 mice, these mice displayed increased levels of apoptosis comparable to those observed in emphysematous Tlr42/2 mice. In conclusion, our data provide in vivo evidence for the non-essential role for TLR2, unlike the related TLR4, in maintaining the normal architecture of the lung. In addition, we reveal that Mal differentially facilitates the anti-apoptotic, but not oxidant suppressive, activities of TLR4 in the lung, both of which appear to be essential for TLR4 to prevent the onset of emphysema

Validation of the anti-inflammatory properties of small-molecule IκB kinase (IKK)-2 inhibitors by comparison with adenoviral-mediated delivery of dominant-negative IKK1 and IKK2 in human airways smooth muscle

Asthma and chronic obstructive pulmonary disease (COPD) are characterized by chronic airway inflammation. However, because patients with COPD and certain patients with asthma show little or no therapeutic benefit from existing corticosteroid therapies, there is an urgent need for novel anti-inflammatory strategies. The transcription factor nuclear factor-κB (NF-κB) is central to inflammation and is necessary for the expression of numerous inflammatory genes. Proinflammatory cytokines, including interleukin (IL)-1β and tumor necrosis factor (TNF)-α, activate the IκB kinase complex (IKK) to promote the degradation of inhibitory IκB proteins and activate NF-κB. This pathway and, in particular, the main IκB kinase, IKK2, are now considered prime targets for novel anti-inflammatory drugs. Therefore, we have used adenoviral overexpression to demonstrate NF-κB and IKK2 dependence of key inflammatory genes, including intercellular adhesion molecule (ICAM)-1, cyclooxygenase-2, IL-6, IL-8, granulocyte macrophage-colony-stimulating factor (GM-CSF), regulated on activation normal T cell expressed and secreted (RANTES), monocyte chemotactic protein-1 (MCP-1), growth-regulated oncogene-α (GROα), neutrophil-activating protein-2 (NAP-2), and epithelial neutrophil activating peptide 78 (ENA-78) in primary human airways smooth muscle cells. Because this cell type is central to the pathogenesis of airway inflammatory diseases, these data predict a beneficial effect of IKK2 inhibition. These validated outputs were therefore used to evaluate the novel IKK inhibitors N-(6-chloro-9H-β- carbolin-8-yl) nicotinamide (PS-1145) and N-(6-chloro-7-methoxy-9H-β- carbolin-8-yl)-2-methyl-nicotinamide (ML120B) on IL-1β and TNFα-induced expression, and this was compared with the corticosteroid dexamethasone. As observed above, ICAM-1, IL-6, IL-8, GM-CSF, RANTES, MCP-1, GROα, NAP-2, and ENA-78 expression was reduced by the IKK inhibitors. Furthermore, this inhibition was either as effective, or for ICAM-1, MCP-1, GROα, and NAP-2, more effective, than a maximally effective concentration of dexamethasone. We therefore suggest that IKK inhibitors may be of considerable benefit in inflammatory airways diseases, particularly in COPD or severe asthma, in which corticosteroids are ineffective. Copyright © 2006 The American Society for Pharmacology and Experimental Therapeutics

Repair of giant midline abdominal wall hernias: "components separation technique" versus prosthetic repair : interim analysis of a randomized controlled trial.

Contains fulltext : 51559.pdf (publisher's version ) (Closed access)BACKGROUND: Reconstruction of giant midline abdominal wall hernias is difficult, and no data are available to decide which technique should be used. It was the aim of this study to compare the "components separation technique" (CST) versus prosthetic repair with e-PTFE patch (PR). METHOD: Patients with giant midline abdominal wall hernias were randomized for CST or PR. Patients underwent operation following standard procedures. Postoperative morbidity was scored on a standard form, and patients were followed for 36 months after operation for recurrent hernia. RESULTS: Between November 1999 and June 2001, 39 patients were randomized for the study, 19 for CST and 18 for PR. Two patients were excluded perioperatively because of gross contamination of the operative field. No differences were found between the groups at baseline with respect to demographic details, co-morbidity, and size of the defect. There was no in-hospital mortality. Wound complications were found in 10 of 19 patients after CST and 13 of 18 patients after PR. Seroma was found more frequently after PR. In 7 of 18 patients after PR, the prosthesis had to be removed as a consequence of early or late infection. Reherniation occurred in 10 patients after CST and in 4 patients after PR. CONCLUSIONS: Repair of abdominal wall hernias with the component separation technique compares favorably with prosthetic repair. Although the reherniation rate after CST is relatively high, the consequences of wound healing disturbances in the presence of e-PTFE patch are far-reaching, often resulting in loss of the prosthesis

Reconstrução abdominal tardia sem tensão após laparostomia: uma nova técnica

OBJETIVO: A reconstrução abdominal tardia após laparostomia é sempre um procedimento desafiador para o cirurgião devido à necessidade de se corrigir um grande defeito na parede abdominal anterior, o que habitualmente demanda a lise de extensas aderências entre alças intestinais e o tecido cicatricial, sem que a hérnia incisional seja o resultado final. Neste trabalho, propomos uma técnica simples e inédita para esta reconstrução abdominal, sem tensão, utilizando tela de polipropileno sobre o tecido de granulação, sem necessidade de qualquer dissecção intra-peritoneal. MÉTODO: Descrição da técnica e estudo prospectivo de 17 pacientes submetidos à mesma entre 1998 e 2005. Foram analisados; a causa da laparostomia, o tempo entre a laparostomia e a reconstrução, o tempo operatório e a evolução pós-operatória imediata e tardia incluindo a incidência de hérnias incisionais. RESULTADOS: A idade média dos pacientes foi de 41 anos. As indicações da laparostomia foram; peritonite em oito pacientes, trauma abdominal em outros oito e pancreatite necrotizante em um. O tempo médio até a reconstrução abdominal foi de 14 meses. O tempo médio do procedimento cirúrgico foi de 130 minutos. O período médio de internação hospitalar foi de 2,6 dias para os 15 pacientes sem complicações pós-operatórias. Não houveram óbitos ou ocorrência de síndrome de compartimento abdominal relacionados à técnica. A média do período de acompanhamento pós-operatório é de 24 meses e até o momento não há ocorrência de hérnia incisional em todo o grupo. CONCLUSÕES: A técnica aqui proposta é de fácil execução e reprodutibilidade, torna desnecessária a manipulação da cavidade abdominal com conseqüente diminuição do risco de lesão de vísceras abdominais e proporciona o fechamento definitivo da laparostomia sem tensão. Esta técnica não acarretou síndrome de compartimento abdominal e nenhum paciente desenvolveu hérnia incisional até o momento