Research in my laboratory focuses on pulmonary toxicology and lung disease. Particular emphasis is on the activity and inhibition of pulmonary surfactant, a complex mixture of phospholipids and specific proteins required for normal breathing. A deficiency in lung surfactant in premature infants is responsible for the respiratory distress syndrome (RDS), a major cause of neonatal mortality worldwide. In addition, lung surfactant inactivation is an important contributor to the lethal acute respiratory distress syndrome (ARDS), associated with lung injury following shock, trauma, infection, radiation toxicity, oxygen toxicity, acid aspiration, drug overdoses, and many other causes.

       Our basic laboratory research studies the surface activity and molecular biophysics of pulmonary surfactant, and how it can be inactivated by inhibitors during acute lung injury. We also study how endogenous surfactant can be replaced or supplemented with active exogenous substitutes in animals and humans with RDS and ARDS. These studies incorporate a spectrum of biophysical, biochemical, and physiological research, along with clinical medicine and pharmacology.

       Our research examines the surface active interactions of a range of natural and synthetic lung surfactant materials, including biologic phospholipids, synthetic phospholipid analogs, synthetic hydrophobic peptides, purified surfactant proteins, phospholipid subfractions of native surfactant, and clinical exogenous surfactant drugs. Complementary experimental techniques are used to study adsorption and dynamic surface tension lowering behavior, as well as mechanisms of surfactant inactivation by plasma proteins, membrane lipids, lytic enzymes, and other compounds in lung injury. Molecular interactions of different surfactant components are studied further at the molecular level using Fourier transform infrared spectroscopy, differential scanning calorimetry, Brewster-angle microscopy, and related methods. Physiological studies focus on mechanisms of lung surfactant dysfunction and deficiency in animal models of acute lung injury and their treatment with exogenous surfactants.

       In addition to basic science understanding, an important goal of our overall research program is the identification and development of optimal synthetic lung surfactants and treatment protocols for use in patients, with final evaluations done in controlled clinical trials at the University of Rochester and other academic medical centers. Our research program at Rochester over the past two decades has helped to develop successful clinical surfactant therapy for RDS in infants, and this is now being optimized and extended to acute lung injury and ARDS.

Selected Recent Publications

Hickman-Davis J, Wang Z, Fierro-Perez GA, Chess PR, Page GP, Matalon S, Notter RH. 2006. Surfactant Dysfunction in SP-A(-/-) and iNOS (-/-) Mice with Mycoplasma Infection. Am J Respir Cell Mol Biol. 2006 Aug 17; [Epub ahead of print]

Bruckner L, Gigliotti F, Wright T, Harmsen A, Notter RH, Chess P, Wang Z, Finkelstein J. 2006. Pneumocystis carinii infection sensitizes lung to radiation-induced injury after syngeneic marrow transplantation: role of CD4+ T cells. Am J Physiol Lung Cell Mol Physiol. Jun;290(6):L1087-1096.

Hutson AD, Davidson BA, Raghavendran K, Chess PR, Tait AR, Holm BA, Notter RH, Knight PR. 2006. Statistical prediction of the type of gastric aspiration lung injury based on early cytokine/chemokine profiles. Anesthesiology. Jan;104(1):73-79.

Raghavendran K, Davidson BA, Helinski JD, Marschke CJ, Manderscheid P, Woytash JA, Notter RH, Knight PR. 2005. A rat model for isolated bilateral lung contusion from blunt chest trauma. Anesth Analg. Nov;101(5):1482-1489.

Hutson AD, Davidson BA, Raghavendran K, Chess PR, Tait AR, Holm BA, Notter RH, Knight PR. 2006. Statistical prediction of the type of gastric aspiration lung injury based on early cytokine/chemokine profiles. Anesthesiology. Jan;104(1):73-9.

Chang Y, Wang Z, Schwan AL, Wang Z, Holm BA, Baatz JE, Notter RH. 2005. Surface properties of sulfur- and ether-linked phosphonolipids with and without purified hydrophobic lung surfactant proteins. Chem Phys Lipids. Oct;137(1-2):77-93.

Raghavendran K, Davidson BA, Woytash JA, Helinski JD, Marschke CJ, Manderscheid PA, Notter RH, Knight PR. 2005. The evolution of isolated bilateral lung contusion from blunt chest trauma in rats: cellular and cytokine responses. Shock. Aug;24(2):132-138.

Wang Z, Foye A, Chang Y, Chess PR, Wright TW, Bhagwat S, Gigliotti F, Notter RH. 2005. Inhibition of surfactant activity by Pneumocystis carinii organisms and components in vitro. Am J Physiol Lung Cell Mol Physiol. Jun;288(6):L1124-1131

Raghavendran K, Davidson BA, Mullan BA, Hutson AD, Russo TA, Manderscheid PA, Woytash JA, Holm BA, Notter RH, Knight PR. 2005. Acid and particulate-induced aspiration lung injury in mice: importance of MCP-1. Am J Physiol Lung Cell Mol Physiol. Jul;289(1):L134-143.

Davidson BA, Knight PR, Wang Z, Chess PR, Holm BA, Russo TA, Hutson A, Notter RH. 2005. Surfactant alterations in acute inflammatory lung injury from aspiration of acid and gastric particulates. Am J Physiol Lung Cell Mol Physiol. Apr;288(4):L699-708

Shanmukh S, Biswas N, Waring AJ, Walther FJ, Wang Z, Chang Y, Notter RH, and Dluhy RA. 2005. Structure and properties of phospholipid-peptide monolayers containing monomeric SP-B(1-25) II. Peptide conformation by infrared spectroscopy. Biophys Chem. Mar 1;113(3):233-244.

Biswas N, Shanmukh S, Waring AJ, Walther F, Wang Z, Chang Y, Notter RH, Dluhy RA. 2005. Structure and properties of phospholipid-peptide monolayers containing monomeric SP-B(1-25) I. Phases and morphology by epifluorescence microscopy. Biophys Chem. Mar 1;113(3):223-232.

Chang Y, Wang Z, Notter RH, Wang Z, Qu L, and Schwan AL. 2004. Synthesis and interfacial behavior of sulfur-containing analogs of lung surfactant dipalmitoyl phosphatidylcholine. Bioorg Med Chem Lett. Dec 20;14(24):5983-5986

Knight PR, Davidson BA, Nader ND, Helinski JD, Marschke CJ, Russo TA, Hutson AD, Notter RH, and Holm BA. 2004. Progressive, severe lung injury secondary to the interaction of insults in gastric aspiration. Exp Lung Res. Oct-Nov;30(7):535-557.

Notter, R.H. 2000. Lung surfactants: Basic science and clinical applications. New York: Marcel Dekker, 444 pages.