Oxygen-Modulated, Isoprostane-Induced Pulmonary Edema
Name: Charles Vacchiano
Rank: LCDR, USN
Organization: Medical University of South Carolina
Performance Site: Medical University of South Carolina, Charleston, SC
Year Published: 1993
Abstract Status: Initial
In humans and animals, oxygen exposure of sufficient duration and partial pressure can induce pulmonary edema and associated hypoxemia, both hallmarks of Adult Respiratory Distress Syndrome (ARDS). Patients with pulmonary edema arising from other causes such as inhalation of toxins, multiple trauma, and sepsis are frequently treated with high concentrations of oxygen. Combat casualties and civilian trauma victims are two large populations at risk for this scenario of adding insult to injury by treating pathologies which may manifest themselves as ARDS with an agent known to cause ARDS when applied in high continuous concentrations. The specific cellular and molecular mechanism of oxygen toxicity are unknown. It is possible that a final common pathway exists for ARDS of multiple etiologies. There is evidence to suggest that alveolar macrophages (AM) play an important role in the early exudative phase of hyperoxic lung injury through synthesis of prostaglandins. Macrophages generate free radicals using oxygen as the substrate. Free radicals can catalyze lipid peroxidation of available phospholipids which has recently been associated with the non-enzymatic production of vasoactive isomeric prostaglandin compounds (Isoprostanes). One of these compounds, 8-Isoprostane, can produce severe pulmonary vasoconstriction, the incipient event in ARDS of multiple causes. This activity is coincident with the movement of a proteinaceous exudate into the interstitial and intra-alveolar spaces. This investigation proposes to examine the cellular and molecular mechanisms of oxygen generated pulmonary injury by: (1) quantitating the duration of exposure and oxygen concentration necessary to elaborate Isoprostanes from AMs; (2) determining the relationship between formation of reactive oxygen species and the availability of lipid substrates to production of Isoprostanes by AMs. These specific aims will be examined with the following methods: (1) isolation and primary culture of rat alveolar macrophages; (2) incubation of cell populations in air and incremental concentrations of oxygen for increasing time periods; (3) exposure of cell cultures to various stimulants; (4) superoxide dismutase inhibitable cytochrome c assay for superoxide anion; and (5) enzyme immunoassay for 8-Isoprostane.