© 2004 American Thoracic Society
Only Cell and Molecular Biology Can Lead to an Understanding of Pathogenesis of Lung DiseaseMaurice B. Strauss, Professor of Medicine Boston University School of Medicine Boston, Massachusetts Many branches of science are useful in investigating human disease. Physiology identifies and measures abnormalities of function. Correcting a functional abnormality, such as hypoxemia with oxygen therapy, can preserve life while the lung undergoes healing. Correction of chronic hypoxemia by long-term oxygen therapy in chronic obstructive pulmonary disease (COPD) proved to prolong life (1). Epidemiologic studies established that tobacco smoking was a major risk factor for COPD, lung cancer, and cardiovascular disease; stopping, or not starting smoking prevented disease (2). Imaging studies permit diagnosis by noninvasive means, help to establish the natural history of disease, and provide surrogates in evaluating the effects of treatment (3). Clinical trials empirically demonstrate the effects of treatment. Although these methods may identify life-saving treatments, reveal important disease associations, and explain disease manifestations, they do not provide information on the cellular mechanisms of disease. Only cell and molecular biology, directed at cell structures, organelles, molecules, or genes and the functional states they determine can lead to an understanding of the fundamental mechanisms of disease. At the midpoint of the twentieth century there were about 20 efficacious drugs in the physician's armamentarium: the opiates, adrenaline, ephedrine, theophylline, digitalis, mercurial diuretics, quinidine, alkaline powders, atropine, sulfonamides, penicillin, streptomycin, mercury salts, salvarsan, bismuth, quinine, oxygen, and anesthetic agents. Today, the average hospital pharmacy stocks about 2,000 drugs, not counting various dosage forms of the same drug. Most of these drugs are efficacious and have enormously enhanced the power of the physician to treat and cure disease. Some of these drugs derived from galenicals or were designed by structural alteration of known drugs. However, a high proportion were derived from cell and molecular studies that identified disease processes and led to targets for drug development. An example of this process is the leukotriene modifier drugs introduced recently for asthma (4). The basic science began with discovery of a mediator, known as slow-reacting substance of anaphylaxis (SRSA) in 1940 (5); SRSA was subsequently shown to be several similar molecules (leukotrienes C4, D4, and E4) derived from arachidonic acid (6). In 1979 and 1980, the chemical structure of SRSA was elucidated (7, 8). The leukotrienes were soon shown to have potent bronchoconstrictor properties as well as an ability to cause tissue edema, the migration of eosinophils, and secretion of mucus—all properties of asthma (9). The pharmaceutical industry became involved. By 1998, zafirlukast, monteleukast, and pranlukast, all leukotriene receptor antagonists, and zileuton, a 5-lipoxygenase inhibitor, had been developed as drugs for asthma (4). It took 50 years after the discovery of SRSA before related drugs were developed. Pulmonary alveolar proteinosis provides an example of an evolving understanding of disease mechanisms. The disease was first described in 1958 (10) as an accumulation within the alveoli of eosinophilic material consisting of lipid, protein, and carbohydrate; cellular infiltration was minimal and alveolar septa were normal. Three distinct forms of the disease were subsequently described: a congenital form due to several gene mutations; a secondary form associated with some hematologic malignancies, inhalation of silica and other toxic substances, pharmacologic immunosuppression, and some infections; and an acquired or idiopathic form which will be our main concern (11, 12). In 1968 it was postulated that the eosinophilic material might be lung surfactant (13) produced in excess, not cleared normally, or structurally abnormal. Because the lung lavage effluent did not lower surface tension, the surfactant theory was not accepted until the early 1980s, when evidence from biochemical, ultrastructural, and physiologic studies became compelling. Surfactant appears to be abnormally cleared rather than produced in excess (11). In 1994 a serendipitous discovery led to a major advance in understanding of alveolar proteinosis (14). Granulocyte/macrophage colony–stimulating factor (GM-CSF) was known to be a hematopoietic growth factor that acts in vitro on myeloid cells, especially eosinophil and neutrophil granulocutes and monocytes/macrophages (15). Knockout mice deficient in GM-CSF showed no defect of hematopoiesis but developed lung disease resembling alveolar proteinosis. The clearance of surfactant protein A and phospholipid were greatly impaired (16). Replacement of GM-CSF in lungs of deficient mice by a variety of means resulted in amelioration of the alveolar proteinosis. Alveolar macrophages from GM-CSF–deficient mice have profound impairment of macrophage immune functions, which are restored by expression of GM-CSF. Deficiency of GM-CSF also results in a diminution of the transcription factor PU-1, which stimulates the terminal differentiation of alveolar macrophages (11). In the human, acquired form of the disease, GM-CSF is elevated in blood and lung fluid, rather than diminished as in the mouse models (17). Trials with subcutaneous recombinant GM-CSF resulted in a favorable response in only about half the patients. Subsequently, it was shown that there is a neutralizing autoantibody to GM-CSF present in serum and lung lavage fluid of all patients with acquired alveolar proteinosis but not in the congenital or secondary forms (18). Human alveolar proteinosis thus appears to be an autoimmune disease. The autoantibody is the basis of a highly specific and sensitive laboratory test for alveolar proteinosis (19). Many questions remain about the pathogenesis of alveolar proteinosis and a fully efficacious treatment is yet to be developed that is less invasive than lung lavage, the current standard of care. Unfortunately, there are many diseases the understanding of which has not progressed to the point where efficacious treatments are on the horizon. Many years of painstaking, expensive work will be necessary if we are to produce effective results; nor do we know the direction from which the desired results will come. Should we severely limit or stop cell and molecular biology studies and confine ourselves to asking easily answered questions with other techniques? If we do, we shall be foreclosing the possibilities of discoveries that began decades earlier and ultimately may lead to major treatments or even a cure. It is essential that we continue with a balanced research portfolio containing a mix of all of the branches of science used to investigate disease. We must continue with cell and molecular biology studies of disease even if the topics studied seem to be esoteric and to have only a tenuous connection to treating or curing a disease (20). Only in this way will we assure advances in treatment for the generations to come. FOOTNOTES Conflict of Interest Statement: G.L.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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