Aging effects on acute lung inflammation after burn injury

描述(由申请人提供)：在65岁以上的人中，中等面积烧伤后并发症和死亡的风险明显更高，而年轻、健康的人几乎不存在。下面概述的研究使用小鼠烧伤模型来帮助确定烧伤后老年人经常发生的肺部并发症的一些机制。我们的假设是，由于老年小鼠在受伤前保持高水平的促炎状态，它们比同等大小的伤口的年轻小鼠更有可能发生肺部炎症，这种炎症反应是局部中性粒细胞趋化因子和血管黏附分子表达增加的结果。在目标1中，我们将通过检测1)中性粒细胞的数量，2)肺水肿的程度，以及3)各年龄组小鼠肺泡屏障功能的变化来评估烧伤后幼龄和老年小鼠肺部炎症的各个方面。该提案的目标2和3将研究烧伤后观察到的中性粒细胞在老年小鼠肺中积累的两种可能机制：增加化学吸引力和增加血管黏附分子的表达。目的2首先测定烧伤后幼鼠和老年小鼠肺中中性粒细胞趋化因子的水平，以确定两个年龄组之间是否存在差异。为了研究这些趋化因子对中性粒细胞渗入肺部的影响，我们将使用抗体来阻断这些因素，并检查烧伤后年轻和老年小鼠的肺部后果，如AIM 1所述。在目标3中，我们将研究烧伤后内皮细胞黏附如何影响肺部炎症。首先，我们将分析烧伤后年轻和老年小鼠肺中血管黏附分子的相对表达水平。为了确定这一过程在调节肺部炎症中是否重要，我们将使用针对血管黏附分子的抗体，并如上所述评估肺部炎症参数的变化。在这项申请中提出的研究对于理解为什么老年患者烧伤后肺部并发症的风险如此之高至关重要。尽管心脏病和癌症仍然位居榜首，但伤害和创伤仍然是我们日益老龄化的人口的一个担忧。揭示老年患者受伤后并发症风险增加背后的机制，可能会揭示新的更好的治疗方案的目标，这些治疗方案可能有助于老年患者在遭受烧伤后完全康复。

DESCRIPTION (provided by applicant): The risk of complications and death after a moderate sized burn injury is significantly higher in persons over the age of 65, while almost non-existent in young, healthy individuals. The studies outlined below use a murine model of burn injury to help determine some of the mechanisms behind the development of pulmonary complications that frequently occur in aged individuals after burn injury. Our hypothesis is that, since aged mice maintain an elevated proinflammatory state prior to injury, they are at an even greater risk of pulmonary inflammation than young mice given a comparable sized wound and that this inflammatory response is a result of increased local production of neutrophil chemokines and expression of vascular adhesion molecules. In aim 1, we will assess various aspects of inflammation in lungs of young and aged mice after receiving a burn injury by examining 1) the number of neutrophils, 2) the degree of pulmonary edema, and 3) changes in the alveolar barrier function in lungs of mice from each age group. Aims 2 and 3 of the proposal will look at two possible mechanisms behind the observed neutrophil accumulation in the lungs of aged mice after burn: increased chemoattraction and higher expression of vascular adhesion molecules. Aim 2 will first involve, measuring levels of neutrophil chemokines in lungs from young and aged mice after burn injury to establish whether differences exist between the two age groups. To study the effects of these chemokines on neutrophil infiltration into the lungs, we will use antibodies to block those factors and examine the pulmonary consequences in young and aged mice after burn, as described in aim1. In aim 3, we will examine how endothelial adhesion affects pulmonary inflammation after burn. Initially we will analyze the relative expression levels of vascular adhesion molecules in the lungs obtained from young and aged mice after burn. To determine whether this process is important in modulating pulmonary inflammation, we will administer antibodies against vascular adhesion molecules and assess changes that occur in the inflammatory parameters in the lung as described above. The studies proposed in this application are critical to understanding why aged patients are at such a higher risk for pulmonary complications after burn injury. Although heart disease and cancer remain at the top of the list, injury and trauma continues to be a concern for our growing aging population. Uncovering the mechanisms behind the increased risk of complications in aged patients after injury may reveal targets for new and better therapeutic regimens that could potentially help older patients reach full recovery after suffering a burn injury.