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Naftali Kaminski, M.D.
Biography

University of Pittsburgh Schools of the Health Sciences 

Advanced Genomics And Proteomics Improve The Diagnosis And Treatment Of A Deadly Lung Disease

University of Pittsburgh study suggests that standard anti-inflammatory therapy may not be appropriate for many interstitial lung disease patients

PITTSBURGH, January 11, 2006 – In an article in the Jan. 15 issue of the American Journal of Respiratory Critical Care Medicine, University of Pittsburgh researchers report that a serious, life-threatening form of pulmonary fibrosis, called idiopathic pulmonary fibrosis, lacks all the hallmarks of inflammation and is probably unnecessarily treated with anti-inflammatory drugs. Moreover, in a related study, the investigators identified a protein found in excess amounts in the lung tissue of patients with idiopathic pulmonary fibrosis, which may be a more appropriate target for therapy.

Interstitial lung disease describes a diverse set of chronic lung conditions that often have strikingly similar symptoms but different clinical courses. However, all are characterized by differing degrees of progressive scarring of lung tissue between the air sacs, or the interstitium. With repeated damage, the interstitium becomes thickened and stiff, or fibrotic, making it increasingly difficult for the individual to breathe. Some forms of interstitial lung disease, particularly idiopathic pulmonary fibrosis, which has no known cause, have a very high death rate due to respiratory failure. Effective treatment, however, is complicated by the fact that a definitive diagnosis often requires a lung biopsy.

“Unfortunately, many patients do not receive lung biopsies. As a result, about one-third of patients who come to our clinic have previously been misdiagnosed, and many have been treated with the wrong medications,” explained James Dauber, M.D., medical director of the University of Pittsburgh’s Dorothy P. & Richard P. Simmons Center for Interstitial Lung Disease, and professor of medicine, division of pulmonary, allergy and critical care medicine .

To improve the diagnosis and treatment of interstitial lung diseases, Naftali Kaminski, M.D., director of the Simmons Center and associate professor of pathology and human genetics, Dr. Dauber, and their coworkers decided to test the effectiveness of DNA microarray chip technology in distinguishing between the gene expression patterns of several types of interstitial lung diseases. Because it can be difficult to obtain lung biopsy samples for some types of interstitial lung disease, the Simmons Center investigators collaborated with researchers in Mexico to obtain samples for another type of pulmonary fibrosis known as hypersensitivity pneumonitis - a pneumonia-like inflammation of the lungs caused by the body's immune reaction to small air-borne particles that is more prevalent in countries such as Mexico where pet birds are common.

Drs. Dauber, Kaminski and their collaborators obtained lung biopsy samples from 15 patients diagnosed with idiopathic pulmonary fibrosis; 12 patients with hypersensitivity pneumonitis; and eight patients with a third, less-understood type, known as nonspecific interstitial pneumonia. The latter is characterized by inflammation and fibrosis that occurs suddenly and progresses rapidly over a relatively short period of time.

When the investigators analyzed the gene expression patterns of the samples using a DNA microarray chip containing sequences for approximately 46,000 known gene clusters—which represent most of the genes in the human genome—the results were startling. Although all of the patients from whom the samples were taken had similar X-ray and laboratory test results, their gene expression patterns were radically different. Indeed, the investigators found that the hypersensitivity pneumonitis samples showed significantly increased expression of genes associated with inflammation, immune cell activation and immune response. In contrast, there was almost no genetic evidence of inflammation in the idiopathic pulmonary fibrosis samples.

“Our results show that interstitial pulmonary fibrosis and hypersensitivity pneumonitis, which clinically often look quite similar, are really two vastly different conditions,” said Dr. Kaminski. “Idiopathic pulmonary fibrosis is characterized by the increased expression of genes involved in the re-growth of lung tissue. So, it is not really an inflammatory condition per se. On the other hand, hypersensitivity pneumonitis does exhibit all of the hallmarks of inflammation, with increased expression of genes that control T-cell activation and immune responses.”

Another surprising finding came when the investigators compared these gene expression patterns to those exhibited by biopsies from the eight patients diagnosed with nonspecific interstitial pneumonia. Two of the eight cases exhibited interstitial pulmonary fibrosis-like gene expression patterns, one closely resembled the gene expression pattern of hypersensitivity pneumonitis, while the other five expression patterns resembled neither. Thus, the investigators were able to reclassify some of the cases of nonspecific interstitial pneumonia using this technology.

In an accompanying editorial, Victor J. Thannickal, M.D., of the University of Michigan and Athol U. Wells, M.D., of the Royal Brompton Hospital in London wrote that although “further studies with greater numbers of patients are required,” these genetic signatures “provide important clues to the observed differences in clinical course, prognosis and responses to therapy in these two disease processes.”

If these findings hold up in larger studies—and Dr. Kaminski is strongly convinced that they will—the diagnosis and management of interstitial lung disease may radically change. In particular, patients with idiopathic pulmonary fibrosis, who are commonly prescribed a course of corticosteroids or other anti-inflammatory drugs as the first line of treatment, will not be subjected to such unwarranted and potentially harmful approaches.

“Until now, the treatment of idiopathic pulmonary fibrosis has been primarily focused on its inflammatory component. However, our findings indicate that lung tissue from these patients does not exhibit a typical inflammatory pattern. So, these patients need to be managed in an entirely new way,” said Dr. Kaminski.

Although there currently is no effective treatment for idiopathic pulmonary fibrosis, results of another study suggest help may soon be on the way. Dr. Kaminski and his colleagues reported in the Sept. 6 online edition of PLoS Medicine that idiopathic pulmonary fibrosis lung tissue samples display an “over-abundance” of a protein known as osteopontin, which other studies have implicated in the growth and progression of tumors. In further examining the potential role of osteopontin in idiopathic pulmonary fibrosis, Dr. Kaminski’s group found that it directly increases the proliferation and movement of fibroblasts, cells centrally involved in lung fibrosis.

“Taken together, these findings are very exciting, because we now have a basis for designing drugs that are specifically directed against osteopontin. By manipulating osteopontin levels, we may be able to slow or stop the course of this deadly disease. In addition, the level of osteopontin may be used as a diagnostic marker for this disease,” explained Dr. Kaminski. He added that his group is currently investigating whether measuring the expression patterns of osteopontin and other genes can predict disease progression and outcome.

In addition to Drs. Kaminski and Dauber, other investigators involved in this research include Kevin Gibson, M.D., Thomas Richards, Ph.D., and Samuel Yousem, M.D., from the University of Pittsburgh; Moises Selman, M.D., Lourdes Barrera, Msc., and Andrea Estrada, M.D., of the Instituto Nacional de Enfermedades Respiratorias in Tlalpan, Mexico; Annie Pardo, Ph.D., of the Facultad de Ciencias, Universidad National Autonoma de Mexico, Mexico City.

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