Mechanisms of MMP-3 Action in Acute Lung Injury

描述（由申请人提供）： 对基质金属蛋白酶-3（MMP-3;基质溶解素-1）基因缺失（MMP-3- /-）动物进行的研究表明，这种酶在急性肺损伤中具有重要的促炎作用，但基质溶解素-1促进疾病过程的机制尚不清楚。MMP-3可能在肺泡壁损伤中起直接作用。肺泡壁损伤本身可能足以促进肺损伤。或者，MMP-3可能通过促进刺激中性粒细胞向肺募集的因子的产生而促进肺损伤。与正常对照组相比，MMP-3 -/-动物中源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产生的趋化细胞因子可能存在差异。拟议研究的总体目标是评估可能的机制，以了解MMP-3如何促进急性肺损伤。在特定目标I中，我们将描述正常小鼠肺中MMP-3的细胞来源，并确定MMP-3水平在急性肺损伤期间的变化。在正常和MMP-3 -/-小鼠中，我们将评估已知在炎症中起作用的几种其他MMP的产生，并将同时评估在相同条件下MMP抑制剂的产生。重要的是要确定在缺乏MMP-3的动物中是否存在其他MMP或MMP抑制剂的代偿性变化。在具体的目标II和III中，我们将利用肺泡壁的体外模型来直接评估MMP-3在肺泡壁损伤中的作用以及MMP-3在中性粒细胞迁移穿过肺泡壁中的作用。研究将在导致完整动物急性肺损伤的条件下和导致中性粒细胞迁移穿过肺泡壁但本身不会导致组织损伤的条件下进行。最后，在特定目标IV中，我们将评估MMP-3在导致急性肺部炎症或导致中性粒细胞流入肺泡腔而无组织损伤的条件下体内肺泡壁损伤中的作用。这些研究将提供对MMP-3促进急性肺损伤的机制的全面理解。

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.