Acute Inflammation Loci Are Involved in Wound Healing in the Mouse Ear Punch Model

Abstract

Molecular biology techniques are being used to aid in determining the mechanisms responsible for tissue repair without scar formation. Wound healing is genetically determined, but there have been few studies that examine the genes responsible for tissue regeneration in mammals. Research using genetic mapping is extremely important for understanding the molecular mechanisms involved in the different phases of tissue regeneration. This process is complex, but an early inflammatory phase appears to influence lesion closure, and the present study demonstrates that acute inflammation loci influence tissue regeneration in mice in a positive manner. Mapping studies of quantitative trait loci (QTL) have been undertaken in recent years to examine candidate genes that participate in the regeneration phenotype. Our laboratory has identified inflammation modifier QTL for wound healing. Mouse lines selected for the maximum (AIRmax) or minimum (AIRmin) acute inflammatory reactivity (AIR) have been used to study not only the tissue repair but also the impact of the genetic control of inflammation on susceptibility to autoimmune, neoplasic, and infectious diseases. Murphy Roths Large and AIRmax mice are exclusive in their complete epimorphic regeneration, although middle-aged inbred mice may also be capable of healing. Inflammatory reactions have traditionally been described in the literature as negative factors in the process of skin injury closure. Inflammation is exacerbated due to the early release of mediators or the intense release of factors that cause cell proliferation after injury. The initial release of these factors as well as the clean-up of the lesion microenvironment are both crucial for following events. In addition, the activation and repression of some genes related to the regeneration phenotype may modulate lesion closure, demonstrating the significance of genetic studies to better understand the mechanisms involved in the initiation of wound repair processes. The pleiotropic effects of the QTL are important in the identification of the genes responsible for tissue repair processes, especially when combined with global gene expression research. Microarray analysis complements the biological information obtained in QTL mapping, making this tool essential for gene identification. This approach will allow the investigation of future targets for therapeutic wound healing treatments.

Oxygen, Metabolism, and Regeneration: Lessons from Mice

“…Specifically, in the ear punch MRL mouse model, macrophages, mast cells, and neutrophils have been shown to be present in increased numbers (39–42) and with increased expression of myeloperoxidase (MPO), and mast cell protease 1 (MCP-1), indicative of inflammatory infiltration at the lesion site (40). Moreover, administration of the cyclooxygenase 2(COX2) inhibitor Meloxicam, an anti-inflammatory agent, was shown to block ear hole closure, confirming that inflammation was required to achieve regeneration (40).…”

“…Moreover, administration of the cyclooxygenase 2(COX2) inhibitor Meloxicam, an anti-inflammatory agent, was shown to block ear hole closure, confirming that inflammation was required to achieve regeneration (40). A compelling study of mice selectively bred for a highly inflammatory phenotype ( AIRmax mouse model ) displayed full ear hole closure and regeneration by contrast to a low inflammation model ( AIRmin ) (42). Here, macrophages were identified and genetic mapping studies revealed that specific alleles of the natural resistance-macrophage protein 1( NRAMP 1), a divalent metal transporter in macrophages, was shown to interact with inflammatory alleles to affect healing (42).…”

“…A compelling study of mice selectively bred for a highly inflammatory phenotype ( AIRmax mouse model ) displayed full ear hole closure and regeneration by contrast to a low inflammation model ( AIRmin ) (42). Here, macrophages were identified and genetic mapping studies revealed that specific alleles of the natural resistance-macrophage protein 1( NRAMP 1), a divalent metal transporter in macrophages, was shown to interact with inflammatory alleles to affect healing (42). In a recent study using the related rodent strain African spiny mouse , depletion of macrophages led to reduced ear hole closure (43,44) supporting a positive macrophage role in the regenerative response.…”

Tendon regeneration and scar formation: The concept of scarless healing

“…There was also a significant genetic linkage of ear hole closure, neutrophil infiltration, and the AIRmax allele of the gene Slc11a1 or Nramp, a protein involved in endosomal ion transport in macrophages and neutrophils. 55 This may play a role in macrophage-enhanced wound healing responses. [56][57][58][59] Considering that the MRL/MpJ mouse retains (subdued) autoimmune features suggested that inflammation might also play a pro-regenerative role here.…”

Influência de Loci reguladores de inflamação aguda na determinação de cicatrização ou regeneração tissular em camundongos geneticamente selecionados para máxima ou mínima resposta inflamatória aguda.

“…Em modelo murino, camundongos da linhagem MRL/Mpj exibiram regeneração epimórfica, semelhante a que ocorre naturalmente nos anfíbios e tornaram-se o modelo mais estudado (CLARK et al, 1998;HEBER-KATZ et al, 2006;HEBER-KATZ et al, 2004;STOCUM, 1995). Contudo, outros estudos foram e estão sendo desenvolvidos demonstrando que esta capacidade regenerativa não é restrita apenas aos camundongos MRL (CANHAMERO et al, 2014;CANHAMERO et al, 2011;DE FRANCO et al, 2007;REINES et al, 2009).…”