David B. Jacoby Professor Medicine Physiology and Pharmacology Chief, Division of Pulmonary and Critical Care Medicine Education AB, Princeton, 1976 MD, New York Medical College, 1980 Research Interests: Our research focuses on viral infections of the lungs and how they cause asthma attacks. We have shown that viruses affect the efferent nerves controlling the airway smooth muscle, as well as airway sensory nerves. In the case of the efferent nerves, there is loss of function of M2 muscarinic receptors on the nerves. These inhibitory receptors normally turn off the release of acetylcholine, thereby limiting reflex bronchoconstriction. Viral infections decrease expression of the gene for this receptor, eliminating the negative feedback control of acetylcholine release and potentiating reflex bronchoconstriction. In collaboration with the laboratory of Dr. Allison Fryer (Department of Physiology and Pharmacology), we have developed methods to study the expression and function of these receptors in primary cultures of airway parasympathetic neurons. We have also cloned the promoter for the M2 receptor gene, and studying the regulation of the gene on this level. Viruses also activate eosinophils (which adhere to the airway nerves in patients with asthma), causing them to release proteins that bind to M2 receptors, blocking their function. We are investigating the recruitment of eosinophils by chemokines produced by nerves, as well as the anchoring and activation of eosinophils by adhesion molecules on the nerves. We have also observed that eosinophils have an unexpected antiviral effect in the lungs. The mechanisms of this virus killing, and in particular the role of metabolism of bromide by eosinophil peroxidase, are another focus of our studies. Sensory nerves are also affected by viral infections. Expression of tachykinins (proinflammatory neuropeptides) is increased, while a major enzyme responsible for inactivating tachykinins, neutral endopeptidase, is decreased. Our ongoing studies include investigations of the mechanisms of virus induced neural plasticity.   Representative Publications Fryer AD, Jacoby DB. The function of pulmonary M2 muscarinic receptors in antigen-challenged guinea pigs is restored by heparin and poly-l-glutamate. J Clin Invest 90:2292-2298, 1992. Jacoby DB, Gleich GJ, Fryer AD. Human eosinophil major basic protein is an endogenous allosteric antagonist at the inhibitory muscarinic M2 receptor. J Clin Invest 91:1314-1318, 1993. Costello RW, Schofield BH, Gleich GJ, Kephardt G, Jacoby DB, Fryer AD. Recruitment of eosinophils to airway nerves inhibits M2 receptor function in antigen challenged guinea pigs. Am J Physiol, Lung Cell Mol Physiol 273:L93-L103, 1997. Jacoby DB, Xiao H-Q, Lee N, Chan-Li Y, Fryer AD. Virus- and interferon-induced loss of inhibitory M2 muscarinic receptor function and gene expression in cultured airway parasympathetic neurons. J. Clin Invest. 102:242-248, 1998. Adamko, DA, Yost BL, Gleich GJ, Fryer AD, Jacoby DB. Ovalbumin sensitization changes the inflammatory response to subsequent parainfluenza infection: eosinophils mediate airway hyperresponsiveness, M2 muscarinic receptor dysfunction, and antiviral effects. J Exp Med 190:1465-1478, 1999. Jacoby DB, Elwood T, Yost BL, Fryer AD. Neurokinin receptor antagonists in virus-infected airways: Dissociation of effects on inflammation and hyperresponsiveness. Am. J. Physiol.: Lung Cell. Mol. Physiol. 279:L59-65, 2000 Jacoby DB, Yost BL, Kumaravel B, Chan-Li Y, Xiao H-Q, Kawashima K, Fryer AD. Glucocorticoid treatment increases inhibitory M2 muscarinic receptor expression and function in the airways. Am J Respir Cell Mol Biol. 24:485-491, 2001 Zhou C, Fryer AD, Jacoby DB. Structure of the M2 muscarinic acetylcholine receptor gene and its promoter. Gene 271:87-92, 2001. Jacoby DB. Virus-induced asthma attacks. JAMA, 287:755-761, 2002. Adamko DJ, Fryer AD, Bochner BS, Jacoby DB. CD8+ T lymphocytes in viral hyperreactivity and M2 muscarinic receptor dysfunction. Am J Respir Crit Care Med. 167:550-556, 2003 For a more complete bibliography, see the following These pages last updated 2-03-04