Clearing the path ahead

Goblet cell metaplasia results in excessive amounts of mucus in people with chronic bronchitis, cystic fibrosis, and asthma. A person’s persistent inability to clear that mucus is a major contributor to their difficulty in breathing. In a recent publication in the Journal of Clinical Investigation, Alejandro Pezzulo, MD, Assistant Professor in Pulmonary, Critical Care, and Occupational Medicine, has identified a treatment that reverts airway goblet cell metaplasia and restores normal numbers of mucus-clearing ciliated cells.

pezzulo_1-30-19aDr. Pezzulo and his colleagues used computational biology methods to identify candidate compounds that revert the goblet cell excess regardless of the initial disease process. This approach pointed to inhibitors of heat-shock protein 90 (HSP90) as promising agents. They tested the HSP90 inhibitor geldanamycin on both human cultured airways and in mice and found that the drug could reverse the metaplasia, decreasing the excess of mucus-secreting goblet cells, and restoring the normal numbers of mucus-clearing ciliated cells. “Chronic goblet cell metaplasia has no treatments,” Dr. Pezzulo said, “and targeting HSP90 has the potential to relieve people with chronic bronchitis and other lung diseases from excessive airway mucus.”

pezzulo_1-30-19bThe JCI publication is the result of years of steady work on Dr. Pezzulo’s part. Almost two years ago, six months before finishing his pulmonary and critical care fellowship at Iowa, Dr. Pezzulo received the prestigious Parker B. Francis Fellowship in Pulmonary Research. Under the mentorship of Division Director Dr. Joseph Zabner, Dr. Pezzulo examined both HSP90 and histone deacetylase 6 (HDAC6) for their potential involvement in goblet cell metaplasia.

Dr. Pezzulo’s work has not only resulted in this publication, but now also in a five-year, $830,000 K01 award from the NIH’s National Heart, Lung, and Blood Institute. The Mentored Research Scientist Career Development Award will allow Dr. Pezzulo to more closely focus on modulating chronic lung inflammation and understanding how it affects the cellular composition and function of the lungs. Dr. Zabner expressed his admiration for Dr. Pezzulo’s discovery and progression. “Alejandro is an outstanding and diligent scientist and this K-award is an important next step in his career. He is already making great discoveries.”

Other contributors to the JCI publication are Dr. Zabner, Rosarie A. Tudas, Carley G. Stewart, Dr. Luis Vargas Buonfiglio (second-year Internal Medicine resident), Dr. Brian Lindsay, Peter J. Taft, and Nicholas D. Gansemer.

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