40 years of pulmonary and critical care medicine

Washington University was established on principles of high academic excellence and intellectual freedom in 1853. Tradition commenced at the medical school with opening the new Barnes Hospital as a teaching facility dedicated to the School of Medicine in 1914. A clinical faculty of exceptional full time scholars was implemented.

Pulmonary Medicine, as we know it today, began to form in 1919 when surgery, directed by the world renowned Dr. Evarts A. Graham started to dominate the academic program in pulmonary disease at Washington University. The Jewish Hospital, always motivated by the highest ideals, relocated to the vicinity of the School in 1927. The Barnes and Jewish Hospitals merged in 1996. Outstanding pulmonary physicians provided patient care and clinical teaching at both hospitals through the middle decades of the 20th century.

Dr. J. Roger Nelson published important studies on upper and lower airway resistance during the late 1950’s and supervised the pulmonary function laboratory in the Department of Medicine. Dr. Kaye H. Kilburn joined the faculty in July 1961 as Director of the Pulmonary Division but he remained only for one year. Then, Dr. William H. Danforth supervised the laboratory.

Dr. John A. Pierce was recruited as Director of the Division of Pulmonary Medicine in 1967. Teaching programs were active in four hospitals at the time, each with its own faculty. The major programs were at Barnes Hospital where Dr. Goldman was in charge and Jewish Hospital where Dr. Robert M. Senior became Director in 1969. Dr. I.J. Flance supervised the program at St Louis City Hospital until 1967 and Dr. Joseph Levitt directed the Washington University program and the VA Hospital. The fellowship training program started in 1970 and the faculty agreed training should include equal time in each of the 3 teaching hospitals and the fellows should have freedom to choose their research. City Hospital closed in 1985.

The teaching program was expanded through addition of regularly scheduled clinical consultative and teaching conferences. The strength and success of these exercises can be attributed in large measure to the enthusiastic participation of many clinical faculty members who wanted the program to thrive and grow. Aside from Drs. Alfred Goldman, I.J. Flance, and Joseph Levitt, Drs. David Skilling, David Kerr, and Roger Secker-Walker were active. House officers in the Department of Medicine became interested in participating in the program and provided the earliest group of applicants for traineeship. Important scientific advances were occurring in pulmonary division laboratories and the trainees all engaged in research.

Beginning in 1969, a close collaborative effort was established between the research laboratories of Drs. Pierce, Charles Kuhn III of the Department of Pathology, and Dr. Robert M. Senior, Chief of the Pulmonary Division at the Jewish Hospital. The earliest research was directed toward an improved understanding of the relationship between the classic deficiency of alpha1-antitrypsin and the occurrence of panacinar pulmonary emphysema.

Outside funding was required for development of the Division. The American Lung Association of Missouri provided funds for many years. The Division competed successfully for a newly established Program Project Grant from the National Heart, Lung, and Blood Institute in 1973. The grant supports key research projects in the Division. The 5 year grant recently has been renewed for the 7th time, this will keep it in force for 40 consecutive years. Dr. Robert Senior has been the Principal Investigator for the past 25 years. In 1977, the Division was awarded a Training Grant from the NHLBI to provide trainee salary support. Currently under direction of Dr. Michael J. Holtzman, this grant has provided support for more than 30 years. The Division is profoundly grateful and deeply appreciative for the unwavering support and dedication of its greatest benefactors, Mrs. Edith Wolfe and Dr. I.J. Flance.

Initially, the faculty expanded gradually. Drs. Stephen Lefrak and Peter G. Tuteur were recruited in the early 1970’s from the US Air Force Training Program in Pulmonary Disease at Scott Air Force Base in the early 1970’s. Barry Starcher, Ph.D. and Robert Mecham, Ph.D., both experts in elastin biochemistry joined the faculty during the 1970’s and contributed significantly to the research training program. Mecham currently is the Alumni Endowed Professor of Cell Biology and Physiology and continues now as a research leader in the Division. Dr. Erika Crouch joined the group 1983. She discovered pulmonary surfactant D and now is Professor of Pathology. The medical student classes have honored her with numerous teaching awards.

Dr. John A. McDonald joined the Division’s group at the Jewish Hospital in 1979. A biochemist with interests in lung development and fibronectin, he was highly productive in research, and is an excellent physician. He was appointed Director of the Division in 1985 and under his tenure, the Division expanded rapidly. Following McDonald’s departure in 1991, Dr. Michael J. Holtzman was appointed Chief of the Division and the rate of faculty expansion increased further.

Some important accomplishments from the first 25 years deserve mention. Much credit for the work belongs to trainees. Without these dedicated and energetic people, most of the studies never could have happened. Presented below are several examples.

The site of pulmonary surfactant production, a material rich in dipalmityl lecithin (DPL) remained uncertain in 1971. The Clara cell had been suggested as a possible source. A definitive study was done with trititiated palmitate in rats. The authors found no evidence of Clara cell function in surfactant synthesis and concluded the alveolar Type 2 cells synthesize the phospholipid (DPL) component of pulmonary surfactant.

One of our fellows proposed to develop emphysema in experimental animals with highly purified porcine pancreatic elastase since this enzyme, unlike papain (that had been used by others), did not digest collagen. A single instillation of elastase resulted in profound and unequivocal development of emphysema (1973). A technique devised to measure urinary quantities of the cross-linking amino acids desmosine and isodesmosine in elastin proved useful. Elastase purified from human neutrophils was also administered to hamsters intratracheally and produced emphysema. The elastase model was used in many other studies at this center and in other research laboratories in the US and abroad.

The Division was selected by the NHLBI as a site for a national Reference Laboratory for phenotyping alpha1-antitrypsin variants in 1971. The 2 stage typing procedure in use at the time was difficult and tedious. In 1974, isoelectric focusing became available and simplified the typing procedure. The Reference Laboratories provided and confirmed phenotype results, supplied samples of odd types, and instructed interested medical and technical personnel in the technique. The Division laboratory, in collaboration with the other Reference Laboratory produced an illustrated manual that was published (DHEW # NIH 78-1420).

Dr. Edwin K. Silverman completed his Ph.D. thesis in 1990 with a definitive study of gene frequency for the deficiency (PiZ) in 20,000 subjects from St. Louis that he typed personally. To do this, he devised a sophisticated and rapid immunoassay. Data included details from 53 families mostly from the Division series. He proved the previous studies in the US (including one from St. Louis), had drastically underestimated frequency of the deficiency. The Division laboratory continued to determine antitrypsin phenotypes until 1991.

Alveolar macrophages came to be known in the Division as the omnipotent cells, capable of anything. They were shown to have cell surface receptors that specifically facilitate internalization of neutrophil elastase. Receptors were also identified characterized and enumerated for two other neutrophil glycoproteins, lactoferrin and cathepsin G (1982).

A segment of mouse DNA was used as a probe to isolate the human gene for macrophage elastase. Isolated, cloned and characterized, the protein product of the gene is now known as matrix metalloproteinase-12 (MMP-12) [1992]. A cigarette smoking mouse model was used that resulted in the production of emphysema (1997). An MMP-12 knockout mouse was made and exposed to the regular amount emphysema-inducing cigarette smoke but it did not produce emphysema in the MMP-12 knockout mouse. This was strong evidence to support a major role for MMP-12 in the pathogenesis of emphysema

Chemotaxis is an exquisitely sensitive technique for the detection of cell surface receptors. Chemotaxis assays have been utilized by the Division for 30 years. Peptides released from elastin following exposure to elastase were found to exhibit chemotactic activity for monocytes and fibroblasts. Thus, elastin fragments that might appear in the tissues might attract fibroblasts and monocytes to the area of injury.

Alpha1-antitrypsin specifically inhibits neutrophil elastase by forming complexes in a 1:1 molecular ratio. While the interaction permanently neutralizes elastase it cleaves the inhibitor chain into two fragments. The fragments tend to remain associated with the complex but inhibitory activity is lost. The smaller fragment was found to exhibit strong chemotactic activity for polymorphonuclear neutrophils. The significance of this finding remained uncertain until Dr. David Perlmutter’s laboratory at Children’s Hospital discovered a specific receptor they named the serpin-enzyme complex receptor. The receptor leads to upregulation of alpha1-antitrypsin synthesis by the hepatocytes. This is an ingenious feedback mechanism by which destruction of the inhibitor leads to increased production of alpha1-antitrypsin.

In brief, between 1967 and 1992, the Division developed exponentially in many facets and a large cadre of fellows were trained clinically and in research. The Division was well supported and many discoveries were made as the program attained an increasingly important role at the Washington University Medical Center.

In 1992, Dr. Michael J. Holtzman became the Directory of the Pulmonary and Critical Care Medicine and remains in that position at present. During this period, there has been remarkable growth in the scope and depth of divisional clinical, research, and teaching activities.

In the area of clinical activities, the Division has made a number of new initiatives. In particular, the Division has developed a multidisciplinary Lung Center for outpatient activities. This Center also incorporates the outpatient activities of the section of Thoracic Surgery and the Division of Allergy and Immunology. This combination of disciplines allows for comprehensive care of patients with respiratory disorders and has become a model for disease-oriented outpatient practice. In addition, the Division has continued to expand its programs in the areas of Lung Transplantation, Cystic Fibrosis, Pulmonary Vascular Disease, Interstitial Lung Disease, Asthma, Interventional Pulmonology, Sleep Medicine, and Chronic Obstructive Pulmonary Disease.

In the area of medical research, the Division has enjoyed continued growth and development of several cutting-edge programs. There is special emphasis on translational research that draws on the strong basic science at the School and the more recent development of human subject cores and registries to allow for extension of this science to patients with respiratory disease. The Division is now home to three NIH center grants, including an established PPG in lung injury and repair, a new SCCOR program in COPD, and a new AADCRC program in asthma. Divisional funding from extramural sources has grown to approximately $16 million dollars per year and is expected to increase further next year.

The Division’s teaching activities have also expanded. These activities now include not only physician-scientists, but also incorporate an increasing presence in the DBBS and its graduate student program. The Division’s recently renewed NIH training grant in principles of pulmonary research now includes 7 positions for postgraduate trainees and 5 positions for graduate students. Divisional training grant faculty now often hold joint appointments in the basic science departments and can use this resource to enhance the educational experience and opportunity for trainees.

Written by John A. Pierce, MD, and Robert M. Senior, MD