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Acute lung injury occurs as a result of a cascade of cellular events initiated by either infectious or noninfectious inflammatory stimuli. An elevated level of proinflammatory mediators combined with a decreased expression of anti-inflammatory molecules is a critical component of lung inflammation. Expression of proinflammatory genes is regulated by transcriptional mechanisms. Nuclear factor-kappa B (NF-kappa B) is one critical transcription factor required for maximal expression of many cytokines involved in the pathogenesis of acute lung injury. Activation and regulation of NF-kappa B are tightly controlled by a complicated signaling cascade. In acute lung injury caused by infection of bacteria, Toll-like receptors play a central role in initiating the innate immune system and activating NF-kappa B. Anti-inflammatory cytokines such as interleukin-10 and interleukin-13 have been shown to suppress inflammatory processes through inhibiting NF-kappa B activation. NF-kappa B can interact with other transcription factors, and these interactions thereby lead to greater transcriptional selectivity. Modification of transcription is likely to be a logical therapeutic target for acute lung injury.

Beneficial health effects of fruits and vegetables in the diet have been attributed to their high flavonoid content. Dipeptidyl peptidase IV (DPP-IV) is a serine aminopeptidase that is a novel target for type 2 diabetes therapy due to its incretin hormone regulatory effects. In this study, well-characterized anthocyanins (ANC) isolated from berry wine blends and twenty-seven other phenolic compounds commonly present in citrus, berry, grape, and soybean, were individually investigated for their inhibitory effects on DPP-IV by using a luminescence assay and computational modeling. ANC from blueberry-blackberry wine blends strongly inhibited DPP-IV activity (IC50, 0.07 ± 0.02 to >300 μM). Of the twenty-seven phenolics tested, the most potent DPP-IV inhibitors were resveratrol (IC50, 0.6 ± 0.4 nM), luteolin (0.12 ± 0.01 μM), apigenin (0.14 ± 0.02 μM), and flavone (0.17 ± 0.01 μM), with IC50 values lower than diprotin A (4.21 ± 2.01 μM), a reference standard inhibitory compound. Analyses of computational modeling showed that resveratrol and flavone were competitive inhibitors which could dock directly into all three active sites of DPP-IV, while luteolin and apigenin docked in a noncompetitive manner. Hydrogen bonding was the main binding mode of all tested phenolic compounds with DPP-IV. These results indicate that flavonoids, particularly luteolin, apigenin, and flavone, and the stilbenoid resveratrol can act as naturally occurring DPP-IV inhibitors.

Hemorrhagic shock (HS) due to major trauma and surgery predisposes the host to the development of systemic inflammatory response syndrome (SIRS) including acute lung injury (ALI) through activating and exaggerating the innate immune response. IL-1β is a crucial pro-inflammatory cytokine that contributes to the development of SIRS and ALI. Lung endothelial cells (EC) are one important source of IL-1β, and the production of active IL-1β is controlled by the inflammasome. In this study, we addressed the mechanism underlying HS activation of the inflammasome in lung EC. We show that high mobility group box 1 (HMGB1) acting through TLR4, and a synergistic collaboration with TLR2 and RAGE signaling, mediates HS-induced activation of EC NAD(P)H oxidase. In turn, reactive oxygen species (ROS) derived from NAD(P)H oxidase promote the association of thioredoxin-interacting protein (TXNIP) with the Nod-like receptor protein NLRP3 and subsequently induce inflammasome activation and IL-1β secretion from the EC. We also show that neutrophil-derived ROS play a role in enhancing EC NAD(P)H oxidase activation, and therefore an amplified inflammasome activation in response to HS. The present study explores a novel mechanism underlying HS activation of EC inflammasome and, thus, presents a potential therapeutic target for SIRS and ALI induced after HS.