Sustained lung activity of a novel chimeric protein, SOD2/3, after intratracheal administration

Abstract

Delivery of recombinant superoxide dismutase to lung is limited by its short half life and poor tissue penetration. We hypothesized that a chimeric protein, SOD2/3, containing the enzymatic domain of manganese superoxide dismutase (SOD2) and the heparan binding domain of extracellular superoxide dismutase (SOD3) would allow for the delivery of more sustained lung and pulmonary vascular antioxidant activity compared to SOD2. We administered SOD2/3 to rats by intratracheal, (IT) intraperitoneal (IP), or intravenous (IV) routes and evaluated the presence, localization and activity of lung SOD2/3 1 day later using Western blot, immunohistochemistry and SOD activity gel. The effect of IT SOD2/3 on the pulmonary and systemic circulation was studied in vivo in chronically catheterized rats exposed to acute hypoxia. Active SOD2/3 was detected in lung 1 day following IT administration but not detected following IP or IV SOD2/3 administration or IT SOD2. The physiologic response to acute hypoxia, vasoconstriction in the pulmonary circulation and vasodilation in the systemic circulation, was enhanced in rats treated 1 day earlier with IT SOD2/3. These findings indicate that IT administration of SOD2/3 effectively delivers sustained enzyme activity to the lung as well as pulmonary circulation and has a longer tissue half-life compared to native SOD2. Further testing in models of chronic lung or pulmonary vascular diseases mediated by excess superoxide should consider the longer tissue half-life of SOD2/3 as well as its potential systemic vascular effects.Keywords superoxide dismutase; acute hypoxic pulmonary vasoconstriction; SOD2/3

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