This research studies the component-specific molecular biophysics and physiological activity of biological and synthetic pulmonary surfactants. A major goal is to develop new highly active phospholipase-resistant synthetic exogenous surfactants containing novel lipids and peptides for use in the neonatal and acute respiratory distress syndromes (RDS and ARDS). The research also seeks to improve fundamental understanding about surfactant activity and dysfunction.
Aims 1 and 2 examine the surface activity, resistance to inhibition, and P-V mechanical effects in lavaged excised rat lungs of synthetic exogenous surfactants containing novel phospholipase-resistant phospholipid analogs plus synthetic peptides or purified apoproteins. Lavaged calf lung surfactant and current animal-derived clinical surfactants are comparative standards. Complementary biophysical methods are used to fully assess surface-active behavior (Wilhelmy balance, pulsating bubble, adsorption, Brewster-angle microscopy, differential scanning calorimetry, FTIR spectroscopy). Materials studied include synthetic di-ether and ether-thio-phosphonolipids and phospholipids, synthetic regional human-sequence SP-B, SP-C, and SP-A peptides, synthetic glycerophospholipids, and specific lipids and apoproteins purified chromatographically from natural surfactant. Biophysical and excised lung studies in Aims 1, 2 are extended in Aim 3, to define the efficacy of the most active exogenous surfactants in reversing surfactant dysfunction, improving gas exchange, and reducing lung injury in rats with ARDS-related gram negative pneumonitis in vivo. Also studied is the formulation of surfactant dispersions with low shear viscosity to enhance their pulmonary delivery and distribution following tracheal instillation. This integrated hierarchy of biophysical and physiological research will advance basic knowledge about surfactant activity and dysfunction, and define new exogenous surfactants with maximal activity, inhibition resistance, and pulmonary delivery for therapeutic applications.
| National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network; Rice, Todd W; Wheeler, Arthur P et al. (2012) Initial trophic vs full enteral feeding in patients with acute lung injury: the EDEN randomized trial. JAMA 307:795-803 |
| Suki, Béla; Stamenovi?, Dimitrije; Hubmayr, Rolf (2011) Lung parenchymal mechanics. Compr Physiol 1:1317-51 |
| Rice, Todd W; Wheeler, Arthur P; Thompson, B Taylor et al. (2011) Enteral omega-3 fatty acid, gamma-linolenic acid, and antioxidant supplementation in acute lung injury. JAMA 306:1574-81 |
| Raghavendran, Krishnan; Davidson, Bruce A; Hutson, Alan D et al. (2009) Predictive modeling and inflammatory biomarkers in rats with lung contusion and gastric aspiration. J Trauma 67:1182-90 |
| Raghavendran, Krishnan; Notter, Robert H; Davidson, Bruce A et al. (2009) Lung contusion: inflammatory mechanisms and interaction with other injuries. Shock 32:122-30 |
| Yee, Min; Chess, Patricia R; McGrath-Morrow, Sharon A et al. (2009) Neonatal oxygen adversely affects lung function in adult mice without altering surfactant composition or activity. Am J Physiol Lung Cell Mol Physiol 297:L641-9 |
| Raghavendran, Krishnan; Davidson, Bruce A; Huebschmann, John C et al. (2009) Superimposed gastric aspiration increases the severity of inflammation and permeability injury in a rat model of lung contusion. J Surg Res 155:273-82 |
| Raghavendran, Krishnan; Davidson, Bruce A; Knight, Paul R et al. (2008) Surfactant dysfunction in lung contusion with and without superimposed gastric aspiration in a rat model. Shock 30:508-17 |
| Raghavendran, Krishnan; Pryhuber, Gloria S; Chess, Patricia R et al. (2008) Pharmacotherapy of acute lung injury and acute respiratory distress syndrome. Curr Med Chem 15:1911-24 |
| D'Angelis, Christopher A; Holm, Bruce A; Lakshminrusimha, Satyan et al. (2008) Ontogeny of atrial natriuretic peptide and its receptor in the lung: effects on perinatal surfactant release. Pediatr Res 63:239-44 |
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