Dichotomy in duration and severity of acute inflammatory responses in humans arising from differentially expressed proresolution pathways

Abstract

Lipoxins (Lxs) and aspirin-triggered epi-Lxs (15-epi-LxA 4 ) act through the ALX/FPRL1 receptor to block leukocyte trafficking, dampen cytokine/chemokine synthesis, and enhance phagocytic clearance of apoptotic leukocytes-key requisites for inflammatory resolution. Although studies using primarily inbred rodents have highlighted resolution as an active event, little is known about the role resolution pathways play in controlling the duration/profile of inflammatory responses in humans. To examine this, we found two types of responders to cantharidin-induced skin blisters in male healthy volunteers: those with immediate leukocyte accumulation and cytokine/chemokine synthesis followed by early resolution and a second group whose inflammation increased gradually over time followed by delayed resolution. In early resolvers, blister 15-epiLxA 4 and leukocyte ALX were low, but increased as inflammation abated. In contrast, in delayed resolvers, 15-epi-LxA 4 and ALX were high early in the response but waned as inflammation progressed. Elevating 15-epi-LxA 4 in early resolvers using aspirin increased blister leukocyte ALX but reduced cytokines/chemokines as well as polymorphonuclear leukocyte and macrophage numbers. These findings show that two phenotypes exist in humans with respect to inflammation severity/longevity controlled by proresolution mediators, namely 15-epi-LxA 4 . These data have implications for understanding the etiology of chronic inflammation and future directions in antiinflammatory therapy.eicosanoids | inflammation | leukocytes

Validation of the cantharidin‐induced skin blister as an in vivo model of inflammation

“…The absolute number (log transformed) and % of neutrophils (PMN) and eosinophils (PME) measured in the cantharidininduced skin blister were compared by paired t-tests. PDN, methylprednisolone week's interval [12]. Our results show that the intra-subject reproducibility at a 7 days' interval is significant for the total leucocyte count and their differential and for the size of the blisters.This observation is important to validate this technique as a human non-invasive model of innate immunity [2] which could assess the anti-inflammatory properties of novel drugs.…”

“…Recently, the cantharidin-induced blister has been used as tissue injury model to demonstrate that aspirin, at low dose prevents leucocytes from accumulating by triggering epi-lipoxin [4] and that two phenotypes exist with regard to the kinetics of the inflammatory response to cantharidin which are associated with the blocking effect of aspirin [12].Those observations also suggest that the cantharidininduced skin blister could be a promising model to evaluate anti-inflammatory agents in humans.…”

“…Discomfort, without pain, occurs for 2 days over the area of blistering. While the kinetics of leucocyte trafficking is subject-dependent [12], in our experience (see Table 1) the blister diameter and the weight of the liquid obtained at 24 h is very homogeneous between subjects. In our experience, the skin heals within 5 weeks.…”

Papel dos ácidos graxos ômega 3 na resolução dos processos inflamatórios

“…RvE1 diminui a expressão de CD18 em Neutrófilos e Monócitos e modifica a ação da Lselectina (que está relacionada aos eventos iniciais do recrutamento de Leucócitos), resultando na redução da migração de Neutrófilos para o local da inflamação. 2,[54][55][56][57] As resolvinas são produzidas em resposta a um estímulo, têm ação local e têm metabolização por vias enzimáticas que levam à sua inativação. As RvE1 podem ser convertidas a diferentes metabólitos (20-hidroxi-RvE1, 20-carboxi-RvE1, 19-hidroxi-ReV1, 18-oxo-RvE1 e 10, 11-diidro-RvE1) em Neutrófilos humanos que são biologicamente inativos se comparados às RvE1.…”

“…As RvE1 podem ser convertidas a diferentes metabólitos (20-hidroxi-RvE1, 20-carboxi-RvE1, 19-hidroxi-ReV1, 18-oxo-RvE1 e 10, 11-diidro-RvE1) em Neutrófilos humanos que são biologicamente inativos se comparados às RvE1. 2,48,[55][56][57] …”