Project: Research project

Project Details


The overall goal of this application is to fully characterize the
basic biochemical mechanisms which account for the unilateral,
permeability form of pulmonary edema which occurs in re-
expanded lungs. Re-expansion pulmonary edema (RPE) has
traditionally been attributed to forces during expansion which
decrease lung interstitial pressure and lead to transudation of
fluid. Our preliminary data support the hypothesis that the
mechanism of RPE involves oxygen free radical-mediated injury
to alveolar-capillary lining cells during rapid re-expansion and
re-oxygenation of previously collapsed and hypoperfused lungs.
In order to clarify this mechanism, we plan to accomplish the
following specific aims: 1) assessment of the pro-inflammatory
role of 02 metabolites (including superoxide and H2O2) in RPE,
2) study enzymatic and mitochondrial sources of O2 metabolites
along with intracellular antioxidants, 3) investigate the
contribution of neutrophils to the unilateral lung injury, and 4)
isolate and characterize neutrophil chemoattractants produced
during collapse/re-expansion. These experiments will be
accomplished using a rabbit model of re-expansion edema in
which the effects of free radical probes can be tested.
Intracellular antioxidant defenses, especially mitochondrial SOD,
will be assessed before and after re-expansion. The effects of
extracellular superoxide dismutase (SOD) and catalase (CAT) on
edema formation will be tested by intravenous enzyme
pretreatment, and liposome-encapsulated SOD and CAT will be
used to test the effects of augmented intracellular antioxidant
enzymes on edema formation. Additional experiments will be
conducted to determine whether aldehyde oxidase is an
important source of superoxide or H2O2 in this model. Cyanide-
insensitive tissue respiration will be measured as an index of lung
free radical formation. Lung lavage fluid will be assayed for
chemotactic activity and its cellular composition characterized
at various time points before and after re-expansion. The degree
of cytotoxic O2 metabolite production, effects of antioxidants,
and generation of chemoattractants will also be measured in re-
expanded lungs of neutropenic rabbits, to further specify the
contribution of neutrophils. This form of unilateral lung injury
resembles, in many ways, adult respiratory distress syndrome. It
will serve as a model for testing experimental interventions in
acute lung injury, since the internal control lung will greatly
minimize consumption of experimental animals and no exogenous
toxicant need be administered.
Effective start/end date8/1/877/31/92


  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health


  • Medicine(all)


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