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Background Acute lung injury and respiratory distress syndrome is characterized by uncontrolled inflammation of the lungs after a severe inflammatory stimulus. We have previously demonstrated an ameliorated syndrome and improved survival in mice with early administration of valproic acid (VPA), a broad-spectrum histone deacetylase inhibitor, while studies in humans have shown no benefit when anti-inflammatories are administered late. The current study tested the hypothesis that early treatment would improve outcomes in our gram-negative pneumonia-induced acute lung injury. Materials and methods Mice (C57BL/6) had 50 × 106 Escherichia coli (strain 19,138) instilled endotracheally and VPA (250 mg/kg) administered intraperitoneally 3, 4, 6, and 9 h (n = 12/group) later. Six hours after VPA administration, the animals were killed, and bronchoalveolar lavage (BAL) fluid interleukin-6 (IL-6), tumor necrosis factor, neutrophils and macrophages as well as theE coli colony-forming units were quantified. Plasma IL-6 was also measured. A separate group of mice (n = 12/group) were followed prospectively for 7 days to assess survival. Results BAL IL-6 and tumor necrosis factor as well as plasma IL-6 were significantly lower in the animals administered VPA within 3 h (P < 0.05) but not when administered later (4, 6, 9 h). There was no difference in the BAL E coli colony-forming units, macrophage, or neutrophil numbers at any time point. Survival improved only when VPA was administered within 3 h. Conclusions A narrow therapeutic window exists in this murine model of gram-negative pneumonia-induced acute lung injury and likely explains the lack of response in studies with late administration of anti-inflammatory therapies in clinical studies.

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A central characterization of retinal immunobiology is the prevention of proinflammatory activity by macrophages. The retinal pigment epithelial cells (RPEs) are a major source of soluble anti-inflammatory factors. This includes a soluble factor that induces macrophage apoptosis when the activity of the immunomodulating neuropeptide alpha-melanocyte-stimulating hormone (α-MSH) is neutralized. In this manuscript, isolated extracellular soluble membranes (ESMs) from primary RPE were assayed to see if they could be the soluble mediator of apoptosis. Our results demonstrated that RPE ESMs mediated the induction of macrophage apoptosis that was suppressed by α-MSH. In contrast, the RPE line ARPE-19, cultured under conditions that induce similar anti-inflammatory activity to primary RPEs, did not activate apoptosis in the macrophages. Moreover, only the ESMs from primary RPE cultures, and not those from the ARPE-19 cell cultures, expressed mFasL. The results demonstrate that RPE ESMs are a soluble mediator of apoptosis and that this may be a mechanism by which the RPEs select for the survival of α-MSH-induced suppressor cells.