UCSF Profiles

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A. Background
Dr. Nadel obtained pulmonary research training in the Cardiovascular Research Institute at UCSF under Dr. Julius Comroe. In 1968, he was appointed the first Chief of the Division of Pulmonary Diseases in the Department of Medicine. In the 1970s as President of the American Thoracic Society, he successfully lobbied Congress to rename the National Heart Institute the National Heart and Lung Institute. Increased funding for lung research accelerated the pace of lung research. The CVRI attracted young investigators first in Lung Physiology and Pharmacology and then in Cell and Molecular Biology.
B. Early Research
Dr. Nadel has focused research in chronic airway diseases, including asthma, chronic obstructive pulmonary disease (COPD), and Cystic Fibrosis (CF). The serious air pollution crisis in the early 1950s (London Fog, Donora) led to the identification of sulfur dioxide and ozone as important pollutants. Studies by Dr. Nadel and associates characterized the effect of these pollutants and discovered that individuals with obstructive lung diseases were especially sensitive to these inhaled pollutants. Dr. Nadel’s testimony at the State of California committee concerning air pollution standards led to the adoption of the California Standards. Adoption of similar United States Air Pollution Standards followed.
The air pollution studies focused Dr. Nadel’s attention on the regulation of the airways, especially on the epithelium. These pollution studies were carried out at a time when cell biology was evolving. He recognized that inhalation of a variety of materials in the environment could be deleterious to the host (viruses, bacteria, air pollutants, allergens, cigarette smoke). These “invaders” enter the body and are deposited on the surface of the airway epithelium. This led to the understanding that the epithelial defenses must have the capacity to respond to the invaders. This realization led to a series of studies focusing on the epithelium and surrounding cells and their interactions.
One question that arose in the early 1970s was how deposited foreign particulates are cleared from the respiratory tract. Dr. Nadel realized that fluid is required for cilia to clear foreign particulates. A senior colleague, Dr. I. Edelman (who discovered the chloride channel in the kidney), provided expertise that helped the Nadel group to first describe the Na+, Cl¯ exchange mechanism in the airway epithelium that regulates airway epithelial fluid movement (later cloned by other investigators and named CFTR). A series of studies followed that described signaling of the channel and the regulation of water movement.
C. Later Studies
With the evolution of cell biology, a focus on novel molecules in the airways followed. This included studies of arachidonic acid metabolites, including the roles of cyclooxygenase products and 15 lipoxygenase (isolated and cloned by the Nadel lab). Also included were Interleukin 8, cAMP, and mucin (see below).
(1) Antimuscarinic Therapy of Bronchospasm. In the early 1960s, Drs. Nadel and Widdicombe studied the nervous control of airway smooth muscle, showing substantial smooth muscle contractile effects of the muscarinic receptors in the vagus nerves. Subsequent studies associated with the Boehringer-Ingelheim pharmaceutical company resulted in the development anti-cholinergic drugs (Atrovent, and subsequently Tiotropium). Critics of antimuscarinic drugs suggested that an inhibitor of mucin production could be life threatening, which proved to be wrong. The drug has subsequently proven to be effective and successful as a bronchodilator, especially in COPD.
(2) Signaling Pathways for Mucin Production. Mucous hypersecretion has been increasingly recognized to play important roles in obstructive airway diseases, especially by plugging small airways, leading to deterioration and death. Presently, there is no effective therapy available for inhibiting mucin production. In 1999, the Nadel lab discovered that an epithelial growth factor receptor (EGFR) cascade is involved in mucin production by a wide variety of stimuli (Takayama et al., PNAS, 1999). A UCSF patent was obtained and phase two trials are underway.
D. Recent Studies
1. EGFR Signaling Pathways. Recent cell and molecular studies in the Nadel lab have characterized the signaling pathways involved in the regulation of the airway epithelium that modulate a variety of autocrine and paracrine responses. Normal healthy airway epithelial cells respond to exogenous stimuli (for example, viruses, bacteria, cigarette smoke, allergens). These responses include (a) activation of exogenous stimuli by Toll-Like Receptor (TLR)s, (b) activation of oxygen free radicals (ROS), (c) activation of epithelial surface metalloproteinases (e.g., TACE), (d) cleavage of EGFR ligands, and (e) binding of ligands to EGFR, causing EGFR activation and subsequent intracellular signaling. This sequence results in the production of multiple products such as mucins, interleukin 8, (a potent neutrophil chemoattractant), defensins, vascular endothelial growth factor (VEGF), and epithelial cell production. In normal human airway epithelial cells, a variety of stimuli cause only mild activation of EGFR and modest generation of products such as mucins and IL-8. However, stimulation of airway epithelial cells from individuals with chronic airway diseases produces exaggerated amounts of mucins (mucous hypersecretion) and increased amounts of the neutrophil chemoattractant, IL-8. Because exaggerated proinflammatory responses are thought to be deleterious and to cause clinical deterioration in chronic airway diseases, Dr. Nadel’s lab has performed cellular studies to determine the cause of the exaggerated responses.
(1) One mechanism for exaggerated responses is via a secondary feedback pathway that restimulates EGFR. These studies are in an early phase. They describe (a) a CCL20/CCR6 feedback exaggerating mucin production (Kim J. Immunol 2011); and (b) an E prostanoid-3-dependent feedback that exaggerates IL-8 production in airway cancer cells (Kim, Cell Research 2011). This area of investigation is promising and will continue.
(2) Modulation of Proinflammatory Responses. Multiple signaling pathways exist in the epithelial cells. One is the so-called “pro-inflammatory” EGFR pathway. Dr. Nadel and colleagues are presently investigating how activation of one pathway affects other pathways (via reinforcement or via reciprocal actions).
(3) Viral infections are an important source of illness, deterioration of lung function and death. Drs. Nadel and Koff are co-inventors of a method for inhibiting respiratory viral growth. The studies are underway.
(4) CFTR is a molecule that encodes the Cl¯ channel. However, there is also evidence that CFTR on the airway epithelial surface is an inhibitor of inflammatory activity and its absence in Cystic Fibrosis is involved in inflammation in CF. The Nadel lab is studying mechanisms of action of CFTR and its role in inflammatory airway diseases.