Rehman publication, career development award advance CF research

Cystic fibrosis (CF) is one of the most common life-shortening inherited disorders. Previous research, some of which was conducted at the University of Iowa, found that mutations in the gene CFTR cause CF. The protein encoded by this gene forms apical membrane chloride and bicarbonate channels in human airway epithelia. Building off of this research, Tayyab Rehman, MD, clinical assistant professor in Pulmonary, Critical Care and Occupational Medicine, and colleagues published a new article in the Journal of Clinical Investigation titled, “Inflammatory cytokines TNF-α and IL-17 enhance the efficacy of cystic fibrosis transmembrane conductance regulator modulators.”

Rehman’s research focuses on bicarbonate secretion in CF. In newborns with CF, loss of CFTR bicarbonate secretion decreases airway surface liquid (ASL) pH, disrupting host defenses.  Within months of birth, ASL pH in CF increases to normal levels in parallel with progressive increase in airway inflammation. The authors investigated how inflammation alters ASL pH. They studied primary cell culture models and examined the contributions of two inflammatory cytokines, TNF-α and IL-17. They found that the cytokines upregulated a chloride / bicarbonate exchanger pendrin, which increased bicarbonate secretion and alkalinized ASL. However, for similar levels of inflammation, ASL pH in the setting of CF remained abnormally acidic. The inflammatory cytokines also enhanced the response of CF epithelia to approved CFTR modulators. Remarkably, in individuals with CF, airway inflammation correlated with the lung function response to CFTR modulators.

“These findings advance the field in two main ways,” Rehman said. “First, they suggest that inflammation is a key regulator of bicarbonate secretion in CF airways. This is important because it helps explain earlier observations that CF ASL pH increases after birth. The presence of a non-CFTR mechanism to increase bicarbonate secretion offers exciting therapeutic targets, particularly important for individuals who are not candidates for approved CFTR modulators. Second, lung function improvement in response to CFTR modulators is highly variable and not well understood. Our results indicate that airway inflammation modulates the response to CFTR modulators and inflammatory markers may have predictive value.”

Authors on this publication include Philip Karp, Ping Tan, Brian Goodell, Alejandro Pezzulo, Andrew Thurman, Ian Thornell, Samantha Durfey, Michael Duffey, David Stoltz, Edward McKone, Pradeep Singh, and Michael Welsh.

In addition to the publication, Rehman recently received the Harry Shwachman Clinical Investigator Award from the Cystic Fibrosis Foundation. This three-year $390,000 career development award will help Rehman further develop his independent CF research.

“I would like to thank Dr. Michael Welsh for his guidance, support and mentorship on these studies, and the Department of Medicine leadership for supporting my research,” Rehman said.

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