Role of HMGB1 in apoptosis-mediated sepsis lethality

Severe sepsis, a lethal syndrome after infection or injury, is the third leading cause of mortality in the United States. The pathogenesis of severe sepsis is characterized by organ damage and accumulation of apoptotic lymphocytes in the spleen, thymus, and other organs. To examine the potential causal relationships of apoptosis to organ damage, we administered Z-VAD-FMK, a broad-spectrum caspase inhibitor, to mice with sepsis. We found that Z-VAD-FMK–treated septic mice had decreased levels of high mobility group box 1 (HMGB1), a critical cytokine mediator of organ damage in severe sepsis, and suppressed apoptosis in the spleen and thymus. In vitro, apoptotic cells activate macrophages to release HMGB1. Monoclonal antibodies against HMGB1 conferred protection against organ damage but did not prevent the accumulation of apoptotic cells in the spleen. Thus, our data indicate that HMGB1 production is downstream of apoptosis on the final common pathway to organ damage in severe sepsis

Discovery of Novel 2‑((Pyridin-3-yloxy)methyl)piperazines as α7 Nicotinic Acetylcholine Receptor Modulators for the Treatment of Inflammatory Disorders

Herein we report the design, synthesis, and structure–activity relationships for a new class of α7 nicotinic acetylcholine receptor (nAChR) modulators based on the 2-((pyridin-3-yloxy)­methyl)­piperazine scaffold. The oxazolo­[4,5-<i>b</i>]­pyridine, (<b><i>R</i></b>)-<b>18</b>, and 4-methoxyphenylurea, (<b><i>R</i></b>)-<b>47</b>, were identified as potent and selective modulators of the α7 nAChR with favorable in vitro safety profiles and good oral bioavailability in mouse. Both compounds were shown to significantly inhibit cellular infiltration in a murine model of allergic lung inflammation. Despite the structural and in vivo functional similarities in the compounds, only (<b><i>R</i></b>)-<b>18</b> was shown to be an agonist. Compound (<b><i>R</i></b>)-<b>47</b> demonstrated silent agonist activity. These data support the hypothesis that the anti-inflammatory activity of the α7 nAChR is mediated by a signal transduction pathway that is independent of ion current