Inhibition of Toll-like Receptor 4 and the NLPR3 Inflammasome as Potential Treatments for Acute Respiratory Distress Syndrome
Introduction. Acute respiratory distress syndrome (ARDS) results in nearly 75,000 deaths annually in the US,1 with pneumonia, sepsis, and mechanical ventilation frequent causes. Damaged epithelial cells induce inflammation, diffuse alveolar injury, pulmonary infiltrates, and severe hypoxemia. There are no statistically effective pharmacological treatments. Both bacterial and ventilator-induced ARDS share common activation pathways. Ligands binding to TLRs and NLRs initiate the proinflammatory responses,4 activating NF-kB and transcription of cytokines and the NLPR3 inflammasome complex. Research demonstrates that mechanical ventilation and LPS insults increase inflammation and demonstrates a role for the NLRP3 inflammasome in the development of hypoxemia.5 Animal models suggest ventilation caused ARDs involves signaling mediated by TLR 4 and 9. Regulating the TLR to NLRP3 pathway may represent a mechanism to prevent and treat ARDS. Methods. Monoclonal TLR4 antibodies were used to determine how TLR4 triggers inflammation in a mechanical ventillation induced ARDs rat model. Lung injury and inflammation cascade members were analyzed through histological and fluid studies.2 The peptide LR 12 was used as an inhibitor of TREM-1 to examine modulation of LPS-induced ARDS and activation of the NLRP3 inflammasome.3 Isoflurane was investigated as a potential inhibitor of ROS-mediated NLRP3 activation by reducing LPS-induced acute lung injury. A rat model was established by intraperitoneal injection with LPS and a rodent ventilator. To study ROS, rats were injected with IV N-acetylcysteine before LPS injection.4 The TLR4/MyD88 pathway and antibodies in the development of sepsis-associated ARDS, were investigated through a rat model of sepsis using cecal ligation and puncture and anti-TLR4 monoclonal antibodies.6 Results. Stimulating alveolar macrophages with TNF-alpha in the presence of anti-TLR4 Ab eliminated upregulation and secretion of cytokines. Pre-treating rats with anti-TLR4 Ab before mechanical ventilation almost completely eliminated these ventilation-induced changes.2 LR12 reduced mortality and lung pathological changes and suppressed the NLRP3 inflammasome in LPS-induced ALI mice.3 ISO post-treatment was found to protect rats against LPS-induced body weight loss and histopathological damage.4 When pretreated with anti-TLR4 monoclonal antibody, rats exhibited decreased lung injury, inflammatory infiltration, lung edema, and TLR4, TLR9, MYD88 and NF-kB expression.6 Conclusions. The studies provided mechanistic insights into ventilation and bacterial induced ARDS, and identified monoclonal antibody and pharmacological targeting of components of the inflammatory pathway as potential therapies for ARDS. Continuing research in the molecular development of ARDS shows promise for developing future clinical treatments.
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