Reparixin, a Specific Interleukin-8 Inhibitor, Has No Effects on Inflammation during Endotoxemia

Abstract

Reparixin antagonizes interleukin-8 (IL-8) on the level of signal transduction in vitro. We hypothesized that IL-8 mediates some of the reactions occurring during acute inflammation and specifically that IL-8 may be a mediator of endotoxin induced neutrophilia. We therefore tested the effects of reparixin on humoral and cellular parameters in LPS-induced acute systemic inflammation. The study is a randomized (3:2 active:placebo), double-blind, placebo-controlled parallel group trial. Twenty healthy male volunteers randomly received either reparixin (12) or placebo (8) intravenously. One hour after the start ofreparixin/placebo infusion a bolus of2 ng/kg endotoxin was infused over t-2 min. Blood samples were obtained over 24 h. Reparixin, being metabolized to ibuprofen, suppressed serum thromboxane 82 levels by 78% compared to baseline and control at 8 h. LPS-induced neutrophilia was not significantly affected by reparixin in human volunteers. Consistently, reparixin did not alter the lymphocyte or monocyte counts and had no effect on LPS-induced systemic inflammation as measured by tumor necrosis factor alpha (TNF-a) or interleukin-6 (IL-6) release. Regulation of IL-8 receptors CXCRt and 2 and the degranulation marker CDllb showed the expected kinetics. Reparixin had no effect on thrombin formation as measured by prothrombin fragment (F 1 + 2 ) . In conclusion, our study showed that reparixin was safe but had no impact on endotoxin induced inflammation. In contrast to previous studies with its metabolite ibuprofen, reparixin does not enhance inflammation in this model.Reparixin is a small molecule, which is structurally related to the known anti-inflammatory drug ibuprofen. It was developed as a novel, potent and specific inhibitor of the chemokine interleukin-8 (IL-8) on the level of intracellular signal transduction (1). Reparixin acts as a noncompetitive allosteric inhibitor of IL-8 receptors (CXCRI/2) which, by locking CXCR1I2 in an inactive conformation, prevents receptor signalling and human polymorphonuclear leukocyte (PMN) chemotaxis. IL-8 is responsible for several reactions occurring during acute inflammation and is able to induce neutrophilia (2-3). In particular, IL-8 infusion markedly increases neutrophil counts in non-human primates (2). Interleukin-8 induced neutrophilia results from demargination or by a release of neutrophils from bone marrow (3). In circulating monocytes, IL-6 and IL-8 induce tissue factor

Racial differences in endotoxin-induced tissue factor-triggered coagulation

“…TF-mRNA expression of circulating leukocytes was at or below the detection limit of 37.5 amplification cycles in all subjects at baseline (Table 1). Similar to previous trials [18], LPS infusion caused a 14-19 fold increase in TF-mRNA levels after 4 h [19 fold increase (CI: [14][15][16][17][18][19][20][21][22][23][24][25] in Africans vs. 14-fold (CI: 9-18) in Caucasians; P > 0.05 between groups; Fig. 3B].…”

“…During human endotoxemia, neither blockade of tumor necrosis factor (TNF) [22], interleukin‐6 (IL‐6) [23] or IL‐8 [24] alters coagulation. Both groups showed a similar inflammatory response as measured by TNF and IL‐6 [9], which suggests that these factors do not contribute to the observed racial differences in coagulation, and induction of similar TF mRNA levels indicates a preserved general response pattern to LPS.…”

Dipeptidyl Peptidase I-Dependent Neutrophil Recruitment Modulates the Inflammatory Response to Sendai Virus Infection

“…CXCL2 is the mouse homologue of human IL-8, a potent neutrophil chemoattractant that is consistently associated with neutrophilic inflammation during asthma exacerbation (45,46). IL-8 antagonists have been developed; however, in early clinical trials, blockade of IL-8 by itself has no significant effect on inflammation (47). Thus, blockade of neutrophil-derived proteases, such as DPPI, may present an alternative way to reduce chemoattractant levels without compromising the host defense.…”

Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy

“…Repertaxin was originally developed to block CXCL8 activity, and thus reduce tissue damage after myocardial infarction or stroke 210 . A phase I clinical trial has demonstrated that repertaxin is well tolerated in healthy volunteers 211 . Further clinical trials are needed to determine the safety and efficacy of repertaxin in combination with current immunotherapies in patients with cancer.…”