Adverse functions of IL‐17A in experimental sepsis

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. FASEB J. 22, 2198–2205 (2008)Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154352/1/fsb2fj07105221.pd

An essential role for complement C5a in the pathogenesis of septic cardiac dysfunction

Defective cardiac function during sepsis has been referred to as “cardiomyopathy of sepsis.” It is known that sepsis leads to intensive activation of the complement system. In the current study, cardiac function and cardiomyocyte contractility have been evaluated in rats after cecal ligation and puncture (CLP). Significant reductions in left ventricular pressures occurred in vivo and in cardiomyocyte contractility in vitro. These defects were prevented in CLP rats given blocking antibody to C5a. Both mRNA and protein for the C5a receptor (C5aR) were constitutively expressed on cardiomyocytes; both increased as a function of time after CLP. In vitro addition of recombinant rat C5a induced dramatic contractile dysfunction in both sham and CLP cardiomyocytes, but to a consistently greater degree in cells from CLP animals. These data suggest that CLP induces C5aR on cardiomyocytes and that in vivo generation of C5a causes C5a–C5aR interaction, causing dysfunction of cardiomyocytes, resulting in compromise of cardiac performance

Phagocyte-derived catecholamines enhance acute inflammatory injury

It is becoming increasingly clear that the autonomic nervous system and the immune system demonstrate cross-talk during inflammation by means of sympathetic and parasympathetic pathways(1,2). We investigated whether phagocytes are capable of de novo production of catecholamines, suggesting an autocrine/paracrine self-regulatory mechanism by catecholamines during inflammation, as has been described for lymphocytes(3). Here we show that exposure of phagocytes to lipopolysaccharide led to a release of catecholamines and an induction of catecholamine-generating and degrading enzymes, indicating the presence of the complete intracellular machinery for the generation, release and inactivation of catecholamines. To assess the importance of these findings in vivo, we chose two models of acute lung injury. Blockade of alpha(2)-adrenoreceptors or catecholamine-generating enzymes greatly suppressed lung inflammation, whereas the opposite was the case either for an alpha(2)-adrenoreceptor agonist or for inhibition of catecholamine-degrading enzymes. We were able to exclude T cells or sympathetic nerve endings as sources of the injury-modulating catecholamines. Our studies identify phagocytes as a new source of catecholamines, which enhance the inflammatory response.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62733/1/nature06185.pd

Ability of Antioxidant Liposomes to Prevent Acute and Progressive Pulmonary Injury

We recently showed that acute oxidant-related lung injury (ALI) in rats after application of 2-chloroethyl ethyl sulfide (CEES) is attenuated by the airway instillation of antioxidants. We investigated whether intratracheal administration of antioxidant-containing liposomes immediately after instillation of CEES would attenuate short-term as well as long-term (fibrotic) effects of CEES-induced lung injury. In the acute injury model (4 h after injury), N-acetylcysteine (NAC)-containing liposomes were protective and reduced to baseline levels both the lung permeability index and the appearance of proinflammatory mediators in bronchoalveolar lavage fluids from CEES-exposed lungs. Similar results were obtained when rat alveolar macrophages were incubated in vitro with either CEES or lipopolysaccharide in the presence of NAC-liposomes. When lung fibrosis 3 weeks after CEES was quantitated by using hydroxyproline content, liposomes containing NAC or NAC + glutathione had no effects, but liposomes containing α/γ-tocopherol alone or with NAC significantly suppressed the increase in lung hydroxyproline. The data demonstrate that delivery of antioxidants via liposomes to CEES-injured lungs is, depending on liposomal content, protective against ALI, prevents the appearance of proinflammatory mediators in bronchoalveolar fluids, and suppresses progressive fibrosis. Accordingly, the liposomal strategy may be therapeutically useful in CEES-induced lung injury in humans.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63287/1/ars.2007.1878.pd