Goals: Acute Lung Injury (ALI) affects more than 150,000 people every year and more than 80,000 affected people die, with health care costs exceeding $2 billion. The incidence and mortality increase with age, and there is a wide difference in mortality between adults and children. The major goal of this proposal is to identify the key factors that explain the lower mortality in children, in order to identify new strategies to improve outcome of all patients at risk for severe ALI. Localized or systemic infection is the most common cause of ALI, and mechanical ventilation is the most common life-supporting treatment. Experimentally, important synergistic interactions exist between bacterial products and mechanical ventilation in the lungs, leading to more severe lung injury than either factor alone. We have modeled the combined exposure to bacterial products (lipopolysaccharide (LPS)) and mechanical ventilation (MV) in mice, and found that synergistic interactions occur in adult but not in juvenile mice. This leads to the hypothesisthat the decreased incidence and severity of lung injury in children as compared with adults is the result of responses to microbial products and mechanical ventilation that are acquired with age. We will explore this hypothesis in three Specific Aims: 1. To define the relationship between the dose of LPS and the responses of juvenile and adult mice to LPS+MV. 2. To determine whether B-cell leukemia/lymphoma 2 (Bcl2) inhibits interactions between LPS and MV. 3. To determine whether type 1 interferon responses are differentially regulated in juvenile versus adult mice treated with LPS+MV. Approach: We will treat juvenile and adult mice with mechanical ventilation and intrapulmonary bacterial products, alone or in combination for 3 hr, and then use cellular and molecular methods, including gene microarrays and transcriptional activation assays, to measure injury responses in the lungs, the activation of key intracellular signaling pathways and the transcriptional activation of gene clusters important in innate immunity.
These studies will provide important new information about the protective mechanisms that reduce the severity of ALI in juvenile as compared with adult animals. The findings could suggest new strategies for improving the outcome of all patients with severe acute lung injury.