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Although uncontrolled inflammatory response plays a central role in the pathogenesis of acute lung injury (ALI), the precise molecular mechanisms underlying the development of this disorder remain poorly understood. SOCS3 is an important negative regulator of IL-6-type cytokine signaling. SOCS3 is induced in lung during LPS-induced lung injury, suggesting that generation of SOCS3 may represent a regulatory product during ALI. In the current study, we created mice lacking SOCS3 expression in macrophages and neutrophils (LysM-cre SOCS3fl/fl). We evaluated the lung inflammatory response to LPS in both LysM-cre SOCS3fl/fl mice and the wild-type (WT) mice (SOCS3fl/fl). LysM-cre SOCS3fl/fl mice displayed significant increase of the lung permeability index (lung vascular leak of albumin), neutrophils, lung neutrophil accumulation (myeloperoxidase activity), and proinflammatory cytokines/chemokines in bronchial alveolar lavage fluids compared to WT mice. These phenotypes were consistent with morphological evaluation of lung, which showed enhanced inflammatory cell influx and intra-alveolar hemorrhage. We further identify the transcription factor, CCAAT/enhancer-binding protein (C/EBP) δ as a critical downstream target of SOCS3 in LPS-induced ALI. These results indicate that SOCS3 has a protective role in LPS-induced ALI by suppressing C/EBPδ activity in the lung. Elucidating the function of SOCS3 would represent prospective targets for a new generation of drugs needed to treat ALI. [ABSTRACT FROM AUTHOR]

Growing evidence suggests that transcription factor signal transducer and activator of transcription (Stat) 3 may play an important regulatory role during inflammation. However, the function of Stat3 in acute lung injury (ALI) is largely unknown. In the current study, by using an adenoviral vector expressing a dominant-negative Stat3 isoform (Ad-Stat3-EVA), we determined the role of Stat3 in IgG immune complex (IC)-induced inflammatory responses and injury in the lung from C57BL/6J mice. We show that IgG IC-induced DNA binding activity of Stat3 in the lung was significantly inhibited by Stat3-EVA. We demonstrate that both lung vascular permeability (albumin leak) and lung myeloperoxidase accumulation in the Ad-Stat-EVA treated mice were substantially reduced when compared with values in mice receiving control virus (Ad-GFP) during the injury. Furthermore, intratracheal administration of Ad-Stat3-EVA caused significant decreases in the contents of neutrophils, inflammatory cytokines (TNF-α and IL-6), chemokines [keratinocyte cell-derived chemokine, macrophage inflammatory protein (MIP)-1α and MIP-1β], and complement component C5a in bronchoalveolar lavage fluids. Using Stat3-specific small interfering RNA, we show that knocking down Stat3 expression in alveolar macrophages (MH-S cells) significantly reduced the production of proinflammatory mediators on IgG IC stimulation. These data suggest that Stat3 plays an essential role in the pathogenesis of IgG IC-induced ALI by mediating the acute inflammatory responses in the lung and alveolar macrophages. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) in mouse lung occurs after distal airway deposition of IgG immune complexes (IgGICs), resulting in a breakdown of the vascular-airway barrier, causing intrapulmonary edema, hemorrhage, and accumulation of neutrophils [polymorphonuclear leukocytes (PMNs)] in the alveolar compartment, these changes being complement (C5a) and C5a receptor (C5aR) dependent. In this ALI model, C5aR expression (protein) was found to occur on upper (bronchial) and lower (alveolar) airway epithelial cells. An adenovirus construct (siRNA) was used to silence mRNA for C5aR in the lung. Under such conditions, C5aR protein was markedly reduced on lung epithelial cells, resulting in much reduced leakage of albumin into the lung, diminished buildup of PMNs, and lower levels of proinflammatory mediators in bronchoalveolar lavage fluids. These studies indicate that bronchial and alveolar epithelial cell CSaR is up-regulated and greatly contributes to inflammation and injury in the lung. The use of siRNA administered into the airways avoids systemic suppression of C5aR, which might compromise innate immunity. It is possible that such an intervention might be employed in humans with ALI or acute respiratory distress syndrome as well as in upper-airway inflammatory diseases, such as chronic obstructive pulmonary disease and asthma, where there is evidence for complement activation and buildup of PMNs. [ABSTRACT FROM AUTHOR]

IL-17A is a proinflammatory cytokine produced by a variety of cells. In the current study, we examined the role of IL-17A in sepsis induced in mice by cecal ligation and puncture (CLP). IL-17A levels, which rose time-dependently in plasma after CLP, were not affected in the absence of αβ T cells or neutrophils. In sharp contrast, γδ T cell-knockout or γδ T cell-depleted mice displayed baseline IL-17A plasma levels after CLP. Neutralization of IL-17A by two different antibodies improved sepsis (survival from ∼10% to nearly 60%). Unexpectedly, antibody treatment was protective, even when administration of anti-IL-17A was delayed for up to 12 h after CLP. These protective effects of IL-17A blockade were associated with substantially reduced levels of bacteremia together with significant reductions of systemic proinflammatory cytokines and chemokines in plasma. In vitro incubation of mouse peritoneal macrophages with lipopolysaccharide (LPS) in the copresence of IL-17A substantially increased the production of TNF-α, IL-1β, and IL-6 by these cells. These data suggest that, during experimental sepsis, γδ T cell-derived IL-17A promotes high levels of proinflammatory mediators and bacteremia, resulting in enhanced lethality. IL-17A may be a potential therapeutic target in sepsis.--Flierl, M. A., Rittirsch, D., Gao, H., Hoesel, L. M., Nadeau, B. A., Day, D. E., Zetoune, F. S., Sarma, J. V., Huber-Lang, M. S., Ferrara, J. L. M., Ward, P. A. Adverse functions of IL-17A in experimental sepsis. [ABSTRACT FROM AUTHOR]

Presents findings of a study which investigated the presence and regulation of the second C5a receptor on neutrophils and various organs during sepsis. Evaluation the role for C5L2 nucleotide sequence in balancing the biological responses to C5a; Comparison of 5′-RACE polymerase chain reaction, cyclic DNA cloning and sequence in the rat C5L2 receptor; Contrast between C5L2 and C5aR expression in neutrophils during sepsis; Expression of nRNA for C5L2 during sepsis; Effects of αC5aR and αC5L2 on in vitro and in vivo production of interleukin-6.

Presents a study on the effects of C5a on lipopolysaccharide(LPS)-induced interleukin(IL)-6 generation in neutrophils in vitro and on in vivo IL-6 production in septic rodents. Effects of C5a on LPS-induced IL-6 production and gene transcription; Effects of blockade of C5a/C5a receptor activation on serum IL-6 levels during sepsis; Effects of signaling pathway inhibitors on IL-6 production in neutrophils; Conclusions of the study.