Pulmonary surfactant plays important roles in reducing surface tension at the air-liquid interface of the lung and in regulating lung host defense. In order to carry out these roles, a functional pool of adequate surfactant must be maintained by balancing the rates of secretion and clearance. Studies from our and other laboratories have shown that clearance in the normal lung occurs via reuptake and recycling by type II cells, and via degradation by both type II cells and macrophages. Recently we have focused on understanding the factors that affect surfactant metabolism in the injured or inflamed lung and have discerned that inflammatory cells and bacterial products contribute significantly to surfactant degradation. Our recent preliminary data show that Pseudomonas aeruginosa, an important pulmonary pathogen, degrades SP-A and SP-D and we have identified enzymes, including Pseudomonas elastase, that contribute to this process. In addition, our preliminary data suggest that neutrophils and activated macrophages contribute substantially to surfactant degradation. The hypothesis to be tested in this competitive renewal is that infection and inflammation result in release of degradative enzymes from bacteria and from newly recruited inflammatory cells that result in enhanced degradation and decreases in surfactant pool size. The decrease in the pool of functional surfactant leads to altered lung homeostasis, including decreased lung compliance and increased susceptibility to infection and inflammation.
Five specific aims are proposed to test this hypothesis.
Specific Aim 1 is to determine if bacterial enzymes degrade surfactant lipids and proteins in vitro.
Specific Aim 2 is to determine the role of a newly described P. aeruginosa enzyme, Protease IV, in degrading surfactant.
Specific Aim 3 is to investigate the functional consequences of degradation of surfactant by bacterial enzymes in vitro.
Specific Aim 4 is to determine if surfactant is degraded in vivo.
Specific Aim 5 is to investigate the role of activated macrophages and neutrophils in the degradation of surfactant. Results from these studies will help determine if these mechanisms contribute to the alterations in surfactant pool size that are observed patients with acute lung injury. We propose that degradation of surfactant by bacterial enzymes and cells recruited in response to bacterial infection represent a novel mechanism of pathogen adaptation and manipulation of the host response which would contribute to alterations in surfactant pool size and resulting lung injury. Significance: An understanding of the factors that regulate surfactant metabolism in lung injury and infection should contribute to development of therapies targeted at inhibiting surfactant degradation for treatment of surfactant deficiency of diseases such as ARDS and bacterial pneumonia.
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