Neutrophil Elastase, Mip-2, and TLR-4 Expression During Human and Experimental Sepsis

Abstract

Highly activated neutrophils play a critical role in mediating organ injury in sepsis by releasing neutrophil elastase (NE). Toll-like receptors (TLRs) play an important role in the host defense against invading microbes, and their signaling pathway is critical to the activation of the proinflammatory response. However, the relationship between TLR expression and the host defense mechanism during sepsis has not been fully elucidated. In this paper, we investigated the relationships among chemokine (MIP-2), TLR-4, and NE expression in human sepsis and murine peritonitis (CLP). TLR-4 expression on monocytes/macrophages was examined in patients with sepsis and in murine peritonitis and was markedly increased in both populations. LPS-induced MIP-2 production by bronchoalveolar cells and liver mononuclear cells in mice with peritonitis was also significantly increased compared with sham-operated mice. Pretreatment of the macrophage cell line, RAW 264.7 cells, with a NE inhibitor before their exposure to LPS resulted in a significant dose-dependent decrease in MIP-2 production, which was comparable to that seen following pretreatment with TLR-4 antibody. Furthermore, NE and LPS both up-regulated TLR-4 expression on human peripheral blood monocytes. Thus, chemokine-induced recruitment of neutrophils in sepsis may result in further increased chemokine production and increased expression of TLR-4. Neutrophil-derived NE may be associated with increased expression of monocyte/macrophage TLR-4, thereby serving as a positive feedback loop for the inflammatory response among the different cell populations.

Targeting neutrophil elastase in cystic fibrosis

“…For example, NE upregulates IL8 expression and secretion from bronchial epithelial cells by signalling through toll-like receptor 4 (TLR4) [49,18]. NE- production by the human macrophage cell line RAW 264.7 in a dosedependent manner [50]. NE also upregulates leukotriene B4 (LTB4) secretion from macrophages [51].…”

Sepsis and Acute Kidney Injury

“…30,31 In addition, the expression of TLR-2 and TLR-4 in hepatic and splenic macrophages is significantly increased in mice with experimental peritonitis induced by cecal ligation and puncture. 31,32 These and other findings suggest that modulation of TLRs may become a novel therapeutic target especially in the treatment of organ injury accompanying sepsis. Although this is an interesting approach, it is imperative to note that apart from TLR modulation, sepsis also affects several other pathways including injury caused by endotoxin, complement cascade, coagulation pathway activation, release of arachidonic acid and nitric oxide, vascular injury, and others that mediate the development and course of sepsis.…”

Upregulation of TLR2 and TLR4 in the human adrenocortical cells differentially modulates adrenal steroidogenesis

“…Indeed, during sepsis and septic shock an enhanced TLR expression was already documented e.g. TLR2 and TLR4 in liver (Tsujimoto et al, 2005) or TLR2, TLR4 and TLR9 in peripheral blood (Brandl et al, 2005). This finding is in line with our previous results showing an upregulation of TLR2 and TLR4 in the adrenal glands of mice after injection of lipotechonic acid and LPS (Bornstein et al, 2004b;Zacharowski et al, 2006).…”

“…Significant upregulation of TLRs in various organs e.g. lung, liver, kidney or periphery blood has been reported in different models of sepsis and in critically ill patients (El-Achkar et al, 2006;Tsujimoto et al, 2005;Williams et al, 2003).…”