PSEUDOMONAS ELASTASE AND LUNG INJURY

Research project

Description

Pseudomonas aeruginosa, an opportunistic pathogen, can cause fatal
infections in debilitated or immunocompromised patients. Elastase from
Pseudomonas is a major virulence factor that can cause lung injury and
inflammation. By damaging the epithelium, elastase could increase airway
permeability to proteins, extend infection and alter critical defense
mechanisms. Influx of neutrophils into the lung could potentiate the
injury. This proposal is to study mechanisms of increased epithelial permeability
by Pseudomonas elastase (PE) alone and in combination with activated
neutrophils. PE administered by aerosol to guinea pigs increases
permeability of the pulmonary epithelium, presumably by affecting tight
junctions. Neutrophil (PMN) accumulation in response to a chemotactic
agent also increases epithelial permeability. It is our hypothesis that
both mechanisms contribute to lung injury in bacterial infection. We
will use a guinea pig model to (1) establish the role of PMN in
PE-induced injury; (2) to determine whether influx of PMN occurs in
response to release of IL-8 by PE or other products of Pseudomonas
aeruginosa; (3) to establish whether PE-induced injury, alone or in
combination with PMN, involves disruption of the zonula occludens or
other structures within the junctional complex. Experiments with cultures of guinea pig and rat epithelial cells will
relate PE-induced changes in permeability of cell monolayers to
alteration of junctional proteins, cytoskeletal elements and
extracellular matrix receptors. Cultured cells will be used to determine
if PE alone, or in combination with activated PMN, damages junctional
proteins and thereby alters transepithelial electrical resistance and
permeability to radiolabeled proteins. Other aspects to be explored are:
(1) the relation of junctional components to epithelial barrier function;
(2) the role of the epithelial cytoskeleton in maintenance of the
permeability barrier; (3) the formation and release of PMN activating
cytokines (IL-8) by epithelial cells. The in vitro studies will
complement those in the intact animal and will aid in defining mechanisms
through which PE and other Pseudomonas toxins injure the lung.
StatusFinished
Effective start/end date4/30/923/31/96

Funding

  • National Institutes of Health

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Pancreatic Elastase
Lung Injury
Pseudomonas
Permeability
Guinea Pigs
Neutrophils
Lung
Wounds and Injuries
Proteins
Tight Junctions
Interleukin-8
Pseudomonas aeruginosa
Epithelium
Epithelial Cells
Infection
Cytoskeletal Proteins
Immunocompromised Host
Virulence Factors
Aerosols
Cytoskeleton

Keywords

  • Medicine(all)