Mechanisms of MMP-3 Action in Acute Lung Injury

描述(由申请人提供)： 基质金属蛋白酶-3(MMP3；基质分解素-1)基因缺失动物的研究表明，基质分解酶在急性肺损伤中具有重要的促炎作用，但基质分解酶-1在疾病过程中的作用机制尚不清楚。基质金属蛋白酶-3可能在肺泡壁损伤中起直接作用。肺泡壁本身的损伤可能足以促进肺损伤。或者，基质金属蛋白酶-3可能通过促进刺激中性粒细胞重新聚集到肺中的因子的产生而促进肺损伤。与正常对照组相比，来自细胞外基质非胶原成分的中性粒细胞趋化因子以及巨噬细胞所阐述的趋化细胞因子在MMP-3-/-动物中可能有不同的表达。这项拟议研究的总体目标是评估可能的机制，以了解，具体地说，基质金属蛋白酶-3如何促进急性肺损伤。在特定的目标I中，我们将描绘正常小鼠肺中基质金属蛋白酶-3的细胞来源，并确定在急性肺损伤过程中基质金属蛋白酶-3的水平如何变化。在正常和MMP-3-/-小鼠中，我们将评估其他几种已知在炎症中发挥作用的MMPs的产生，并同时评估相同条件下MMPI的产生。重要的是要确定在缺乏基质金属蛋白酶-3的动物体内是否存在其他基质金属蛋白酶或基质金属蛋白酶抑制物的代偿性变化。在特定的AIMS II和III中，我们将利用肺泡壁的体外模型来直接评估基质金属蛋白酶-3在肺泡壁损伤中的作用，以及基质金属蛋白酶-3在中性粒细胞跨肺泡壁迁移中的作用。研究将在导致完整动物急性肺损伤的条件下进行，并在导致中性粒细胞跨肺泡壁迁移但本身不会导致组织损伤的条件下进行。最后，在特定的第四个目标中，我们将评估在导致急性肺炎症或导致中性粒细胞进入肺泡腔而不造成组织损伤的条件下，基质金属蛋白酶-3在体内肺泡壁损伤中的作用。这些研究将使我们对基质金属蛋白酶-3在急性肺损伤中的作用机制(S)有一个全面的了解。

DESCRIPTION (provided by applicant): Studies conducted with matrix metalloproteinase-3 (MMP-3; stromelysin-1) gene-deleted (MMP-3- /-) animals have indicated an important pro-inflammatory role for this enzyme in acute lung injury, but the mechanism by which stromelysin-1 contributes to the disease process is not well understood. MMP-3 may play a direct role in damage to the alveolar wall. Damage to the alveolar wall, in and of itself, may be sufficient to facilitate lung injury. Alternatively, MMP-3 may promote lung injury by contributing to the generation of factors that stimulate neutrophil recruitment to the lung. Neutrophil chemotactic factors derived from non-collagenous components of the extracellular matrix as well as chemotactic cytokines elaborated by macrophages may be differentially elaborated in MMP-3 -/- animals as compared to normal controls. The overall goal of the proposed research is to evaluate the possible mechanisms in order to understand, specifically, how MMP-3 contributes to acute lung injury. In Specific Aim I, we will delineate the cellular sources of MMP-3 in the lungs of normal mice and determine how MMP-3 levels change during acute lung injury. In normal and MMP-3 -/- mice we will assess the production of several other MMPs that are known to play a role in inflammation and will concomitantly evaluate the production of MMP inhibitors under the same conditions. It is important to determine if there are compensatory changes in other MMPs or MMP inhibitors in animals lacking MMP-3. In specific Aims II and III we will utilize an in vitro model of an alveolar wall to directly assess the role of MMP-3 in damage to the alveolar wall and the role of MMP-3 in neutrophil migration across the alveolar wall. Studies will be conducted under conditions that lead to acute lung injury in intact animals and under conditions that result in neutrophil migration across the alveolar wall occurs but that do not lead to tissue damage, per se. Finally, in Specific Aim IV, we will assess the role of MMP-3 in alveolar wall damage in vivo under conditions that lead to acute lung inflammation or that lead to neutrophil influx into the alveolar space without tissue damage. These studies will provide an overall understanding of the mechanism(s) by which MMP-3 contributes to acute lung injury.