Jay A. Nadel, MD

Jay A. Nadel, MD

Professor, Departments of Medicine, Physiology, and Radiology, UCSF


Phone: (415) 476-1105 (voice)
Box 0130, UCSF
San Francisco, CA 94143-0130

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Cancer Center Membership

Associate Member » Non-aligned

Research Summary

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.


Temple University, Philadelphia, PA, A.B., 1949, Physiology
Jefferson Medical College, Philadelphia, PA, M.D., 1953, Medicine

Professional Experience

  • 1964-present
    Senior Staff Member, Cardiovascular Research Institute, UCSF
  • 1960-1978
    Chief, Pulmonary Function Laboratory, Cardiovasular Research Institute, UCSF
  • 1970-present
    Professor, Department of Medicine, UCSF
  • 1974-present
    Professor, Department of Radiology, UCSF
  • 1977-present
    Professor, Department of Physiology, UCSF
  • 1977-present
    Director, NIH Multidisciplinary Research Training Program in Pulmonary Diseases, CVRI
  • 1979-1997
    Director, NIH Program Project Grant HL-24136
  • 1983-1996
    Director, UCSF Cystic Fibrosis Research Center
  • 1968-1999
    Chief, Section of Pulmonary Diseases, Department of Medicine, UCSF

Honors & Awards

  • 1960
    Gianninni Award
  • 1984
    Clean Air Award, ALA Calif
  • 1984
    California Medal, American Lung Association Calif
  • 1987
    Honorary Member Cal Thoracic Society
  • 1987
    Distinguished Lecturer in Physiology, American College of Chest Physicians
  • 1990
    Pfizer Visiting Professor, Royal Society of Medicine
  • 1991
    Honorary Degree of Medicine and Surgery, University of Ferrara
  • 1992
    Crocker Clean Air Award, American Lung Association
  • 1992
    Sam J. Sills Honorary Lectureship, University of Southern California
  • 1992
    Distinguished Achievement Award, Ben Gurion University
  • 1992
    Robert F. Johnston, M.D., Honorary Lecturer, Philadelphia
  • 1993
    Amberson Honorary Lecturer, American Thoracic Society
  • 1994
    Medal of The University of Helsinki
  • 1994
    Honorary Member, German Society of Pulmonology
  • 1994
    Honorary Member, Finnish Association of Pulmonary Physicians
  • 1996
    Honorary Doctorate of Medicine, University of Lund, Sweden
  • 1997
    Trudeau Medal, American Thoracic Society
  • 1997
    Honorary Degree in Law: Dickinson Law School, Carlisle, PA
  • 1998
    Alumni Achievement Award, Jefferson Medical College (JH Coley Lectureship)
  • 1998
    Best Doctors of America
  • 1999
    Best Doctors of SF Bay Area

Selected Publications

  1. Gelb AF, Nadel JA. Understanding the pathophysiology of the asthma-chronic obstructive pulmonary disease overlap syndrome. J Allergy Clin Immunol. 2015 Sep; 136(3):553-5.
    View on PubMed
  2. Gelb AF, Yamamoto A, Verbeken EK, Nadel JA. Unraveling the Pathophysiology of the Asthma-COPD Overlap Syndrome: Unsuspected Mild Centrilobular Emphysema Is Responsible for Loss of Lung Elastic Recoil in Never Smokers With Asthma With Persistent Expiratory Airflow Limitation. Chest. 2015 Aug 1; 148(2):313-20.
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  3. Kalinowski A, Ueki I, Min-Oo G, Ballon-Landa E, Knoff D, Galen B, Lanier LL, Nadel JA, Koff JL. EGFR activation suppresses respiratory virus-induced IRF1-dependent CXCL10 production. Am J Physiol Lung Cell Mol Physiol. 2014 Jul 15; 307(2):L186-96.
    View on PubMed
  4. Nadel JA. The CFTR and EGFR relationship in airway vascular growth, and its importance in cystic fibrosis. Eur Respir J. 2013 Dec; 42(6):1438-40.
    View on PubMed
  5. Gelb AF, Yamamoto A, Mauad T, Kollin J, Schein MJ, Nadel JA. Unsuspected mild emphysema in nonsmoking patients with chronic asthma with persistent airway obstruction. J Allergy Clin Immunol. 2014 Jan; 133(1):263-5.e1-3.
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  6. Ueki IF, Min-Oo G, Kalinowski A, Ballon-Landa E, Lanier LL, Nadel JA, Koff JL. Respiratory virus-induced EGFR activation suppresses IRF1-dependent interferon ? and antiviral defense in airway epithelium. J Exp Med. 2013 Sep 23; 210(10):1929-36.
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  7. Kim S, Beyer BA, Lewis C, Nadel JA. Normal CFTR inhibits epidermal growth factor receptor-dependent pro-inflammatory chemokine production in human airway epithelial cells. PLoS One. 2013; 8(8):e72981.
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  8. Chung KF, Nadel JA, Fontana G. John Widdicombe's contribution to respiratory physiology and cough: reminiscences. Cough. 2013; 9(1):6.
    View on PubMed
  9. Nadel JA. Mucous hypersecretion and relationship to cough. Pulm Pharmacol Ther. 2013 Oct; 26(5):510-3.
    View on PubMed
  10. Kim S, Lewis C, Nadel JA. Epidermal growth factor receptor reactivation induced by E-prostanoid-3 receptor- and tumor necrosis factor-alpha-converting enzyme-dependent feedback exaggerates interleukin-8 production in airway cancer (NCI-H292) cells. Exp Cell Res. 2011 Nov 1; 317(18):2650-60.
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  11. Kim S, Lewis C, Nadel JA. CCL20/CCR6 feedback exaggerates epidermal growth factor receptor-dependent MUC5AC mucin production in human airway epithelial (NCI-H292) cells. J Immunol. 2011 Mar 15; 186(6):3392-400.
    View on PubMed
  12. Burgel PR, Nadel JA. Epidermal growth factor receptor-mediated innate immune responses and their roles in airway diseases. Eur Respir J. 2008 Oct; 32(4):1068-81.
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  13. Koff JL, Shao MX, Ueki IF, Nadel JA. Multiple TLRs activate EGFR via a signaling cascade to produce innate immune responses in airway epithelium. Am J Physiol Lung Cell Mol Physiol. 2008 Jun; 294(6):L1068-75.
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  14. Nadel JA. Innate immune mucin production via epithelial cell surface signaling: relationship to allergic disease. Curr Opin Allergy Clin Immunol. 2007 Feb; 7(1):57-62.
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  15. Koff JL, Shao MX, Kim S, Ueki IF, Nadel JA. Pseudomonas lipopolysaccharide accelerates wound repair via activation of a novel epithelial cell signaling cascade. J Immunol. 2006 Dec 15; 177(12):8693-700.
    View on PubMed
  16. Shao MX, Nadel JA. Neutrophil elastase induces MUC5AC mucin production in human airway epithelial cells via a cascade involving protein kinase C, reactive oxygen species, and TNF-alpha-converting enzyme. J Immunol. 2005 Sep 15; 175(6):4009-16.
    View on PubMed
  17. Shao MX, Nadel JA. Dual oxidase 1-dependent MUC5AC mucin expression in cultured human airway epithelial cells. Proc Natl Acad Sci U S A. 2005 Jan 18; 102(3):767-72.
    View on PubMed
  18. Nadel JA. COPD. Role of the Airway Epithelium in Defense Against Inhaled Invaders. 2005; 3:285-287.
    View on PubMed
  19. Shao MX, Nakanaga T, Nadel JA. Cigarette smoke induces MUC5AC mucin overproduction via tumor necrosis factor-alpha-converting enzyme in human airway epithelial (NCI-H292) cells. Am J Physiol Lung Cell Mol Physiol. 2004 Aug; 287(2):L420-7.
    View on PubMed
  20. Shao MX, Ueki IF, Nadel JA. Tumor necrosis factor alpha-converting enzyme mediates MUC5AC mucin expression in cultured human airway epithelial cells. Proc Natl Acad Sci U S A. 2003 Sep 30; 100(20):11618-23.
    View on PubMed

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