Despite extensive basic research and clinical studies, effective therapy against sepsis remains lacking. Data from laboratory works conclusively support the concept that restoring the balance of inflammatory network is beneficial against sepsis. However, almost all of these laboratory works failed to prove their effectiveness in clinical studies. One major reason is that these studies mostly were conducted with the design of ‘early interventions’ which is clearly not feasible in clinical situations, as sepsis patients usually do not receive therapies until clinical symptoms and sings become evident. It is thus advocated that therapy that can restore inflammatory network balance after the development of sepsis should be the key element for developing effective therapy against sepsis. Of note, binding of cytokines to receptors is the key step for cytokine signal expression. As production of pro-inflammatory cytokines [e.g., tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1 β) and IL-6] is already increased in sepsis patients, we thus speculate that therapy that can decrease the binding of pro-inflammatory cytokines to receptors can effectively restore inflammatory network balance and provide beneficial effects against sepsis. Peptides are highly selective, efficacious and well tolerated. Based on the binding site structures of cytokine receptors determined from molecular docking simulations, a peptide KIIK18 possessing 3 structures similar to the receptor binding sites of TNF-α, IL-1β and IL-6, respectively has been synthesized. Theoretically, this peptide can be a cytokine binding decoy to capture cytokines and significantly inhibit cytokine-receptor binding, which can restore inflammatory network balance after the development of sepsis. We thus hypothesize that peptide-based cytokine binding decoy therapy using KIIK18 can mitigate hemodynamic alterations, organ dysfunctions and mortality induced by sepsis. To elucidate further, we thus propose this 3-year project. In contrast to those previous studies, this project is design to administer intervention after the development of sepsis. This study will employ in vitro and in vivo sepsis models to facilitate investigations. For in vitro sepsis model, both primary peritoneal macrophages and immortalized macrophages will be stimulated with endotoxin. For in vivo sepsis model, adult male mice will be treated with endotoxin injection (i.e., monomicrobial sepsis) or cecal ligation and puncture (i.e., polymicrobial sepsis). In addition to inflammation, the pathogenesis of sepsis also involves oxidation, apoptosis, autophagy and inflammasomes. This project thus will also investigate the effects of KIIK18 on modulating inflammation, oxidation, apoptosis, autophagy and inflammasomes during sepsis. In addition, peptides are degraded rapidly by proteases and cleared quickly from the bloodstream. Therefore, repeated doses of peptide drugs are required to maintain therapeutic levels. As conjugation with polymers [e.g., polyethylene glycol (PEG) or serum albumin] can effectively enhance the stability of peptides, we will determine the effects of peptide KIIK18 crosslinking with PEG or albumin on its systemic bio-availability. Findings from this project may provide evidence for future development of novel therapies against sepsis.
|Effective start/end date||8/1/17 → 7/31/18|