Cell Stretch as a Physicochemical Secondary Stimulus in Initiating Lipopolysaccharide (LPS)-Mediated Acute Lung Injury

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Acute lung injury (ALI) is an often fatal condition caused by direct or indirect injuries. When the injury occurs directly, eg pneumonia, lung cells release mediators that attract blood cells involved in defending the body. Once in the lungs, these cells are activated and engulf or release reactive molecules that destroy the invading organism a process known as inflammation. When the injury occurs indirectly, eg sepsis, ALI can arise from the spill-over of mediators created elsewhere in the body. Reactive molecules produced can damage the lung barrier separating the blood from the air. Consequently, fluid leaks into the airspaces making breathing difficult and hindering gas exchange. Gram (-) bacteria are the major cause of sepsis, pneumonia, and ALI. The inflammation is initiated by lipopolysaccharide (LPS), the major component of the bacterial cell wall. We have shown that LPS also changes breathing and the distribution of air and blood flow in lungs. This creates localised changes in cell stretch and the amounts of carbon dioxide (CO2) in the airspaces. Previously we showed that cell stretch releases surfactant , a substance that makes breathing easier. We now hypothesise that cell stretch is an important secondary stimulus in initiating ALI. We will use: 1. isolated lung cells to determine which cell types release mediators in response to LPS, and whether: * stretch stimulates their release * release is coordinated between the cell types * release is affected by the amount of CO2 2. isolated lungs to determine whether the pattern of ventilation, blood flow, and amounts of CO2 alter the release of the mediators, and whether these changes affect surfactant secretion and the ability to inflate the lungs. 3. animal models to also determine whether the pattern of respiration changes the course of the respiratory failure. Understanding the mechanisms that cause the disease will lead to better treatments.