The discovery of the importance of PRRs in the pathogenesis of SIRS and organ injury, including ALI, has led to a therapeutic strategy targeting PRRs. TLRs are the most extensively studied family of PRRs, and thus recently developed new drugs mainly target TLRs and are either agonists of TLRs to enhance immune responses against infectious agents or antagonists designed to reduce inflammation due to infection or autoimmune responses (161) . The approaches to modulating TLR activity have focused on the following aspects: (a) ligands or analogues such as Eritoran (E5564) from Eisai (Woodcliff Lake, NJ, USA), a synthetic analogue of bacterial lipid A that inhibits LPS from activating cells through the TLR4/CD14/MD2 complex (162) (163) (164) ; (b) monoclonal antibodies, soluble receptors and other accessory proteins, such as a natural soluble form of TLR2, found in mouse plasma and breast milk, which acts to block TLR2 ligand stimulation (165) , and a member of the TLR/IL-1 receptor family (TIR8 or SIGIRR) that inhibits NF-κB signaling and may be an endogenous inhibitor of the TLR system (166); (c) signal transduction blockers; many of the key molecules in the signaling pathways for each TLR have been identified and are considered potential drug targets (167) (168) (169) . The structural bases of TIR domain interactions between TLRs and adapters such as MyD88, Mal, TRAM and TRIF have been modeled, and small peptidic sequences based on the TIR domain BB loop or peptidomimetics of this region have been made that can block the interactions (110, 169, 170) . (d) siRNA and antisense; studies with knockout mice suggest that deficiency in individual TLRs has limited consequences for animals under normal conditions, but exhibits impact under conditions of specific infectious challenge (110, 171, 172) . However, siRNA sequences themselves may be ligands for intracellular TLRs (173) ; thus attention to the design of appropriate sequences is necessary.