The major physiologic actions of inhaled toxic chemicals on the lung are bronchoconstriction and pulmonary edema. Although these effects are well understood, the absence of specific antidotes has limited the effectiveness of prior therapeutic interventions. As surfactant inactivation and the formation of free radicals are important pathways in acute lung injury and edema, we propose testing synthetic surfactant in rats exposed to highly toxic chemicals. Synthetic surfactant has the advantage of large-scale production and a long shelf-life, and may be readily adapted to optimize resistance against inactivation. Our laboratory has designed, synthesized and characterized several highly-active surfactant protein B (SP-B) and C (SP-C) mimics (mini-B, super-mini-B, maxi-B, and SP-Cff) as a synthetic alternative for the natural lung surfactant preparations currently used in neonatal respiratory distress syndrome (RDS). These synthetic surfactant protein mimics formulated in synthetic lung lavage lipids and phospholipase-resistant phosphatidylcholine (phosphonolipids, e.g. DEPN-8) are under investigation for usefulness in acute RDS (ARDS), which shares many characteristics of lung injury secondary to inhaled highly toxic chemicals.
The specific aims of this application are to: i) synthesize and characterize novel synthetic surfactant mimic proteins and phospholipase-resistant phosphonolipids designed to have high lipid binding, surface activity and inhibition resistance; and ii) to test the in vivo efficacy of an optimized surfactant preparation in rats with acute lung injury induced by exposure to highly toxic gases (e.g., chlorine) or liquids (e.g., hydrochloric acid).
These specific aims will be accomplished using an integrated suite of techniques, including the synthesis of peptide constructs of SP-B and C; solution structure of the SP-B and C peptides by 2D-NMR; monolayer and multilayer FTIR residue-specific structural studies of SP-B and C peptides and proteins; characterization of the surface activity of these constructs in synthetic surfactant lipids by captive bubble surfactometry; and the use of the chlorine/ hydrochloric acid rat model to estimate in vivo efficacy of experimental surfactant on lung function under conditions of surfactant inactivation. These studies should facilitate the development of a synthetic surfactant mixture for treatment of ARDS induced by inhaled toxic chemicals. PROJECT NARRATIVE: Inhalation of toxic chemicals leads to airway damage, bronchoconstriction and severe lung edema secondary to surfactant inhibition and free radical formation. Exogenous surfactant therapy can function as an antidote for lung edema and we propose to develop new synthetic surfactants resistant against inhibition and oxidative stress and test these in rats with life-threatening respiratory disease after exposure to chlorine gas or hydrochloric acid. ? ? ? ? ?
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