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The breakthrough of CFTR modulator therapies to treat CF patients has greatly improved the trajectory of lung disease. However, lung hyper-inflammation is not well controlled by CFTR modulator therapy. Given the substantial role of hyper-inflammation in the pathogenesis of CF-related lung disease, there is a need for aggressive treatments that will prevent the progressive lung tissue deterioration in CF patients.

Our group has ascertained that CF-affected monocyte/macrophages (MΦ) are dysfunctional, contributing to lung hyper-inflammation. We published this pioneering research in the American Journal of Respiratory Cell and Molecular Biology in 2009. Based on these results, we are now investigating the molecular mechanisms associated with CF MΦ dysfunctions.

Ongoing Investigations

Investigating the specific role of Ezrin in MΦ

Expression of EZRIN in macrophages stimulated with LPS

We demonstrated that an actin-binding protein (called Ezrin or Villin-2) fails to localize to the plasma membrane of activated CF MΦs. We published this study in the journal of Scientific Reports in 2017. Little is known about the function of this protein in monocyte/MΦs. We are using mouse models to investigate how ezrin regulates the macrophage immunomodulatory and bactericidal functions during lung infections. We are also investigating the mechanisms and consequences of lower ezrin levels and failure to localize to the plasma membrane in CF-affected MΦ. These studies will deepen understanding of MΦ biology and identify potential targets for therapies against CF lung diseases. This project is supported by NIAID/NIH.

Investigating anti-inflammatory pathways in CF

HO-1 expression in alveolar macrophages in human lungs
The non-resolving hyper-inflammation in CF lungs is attributed to an impairment of several signaling pathways associated with resolution of the inflammatory response.Among these, we have ascertained that CF macrophages have an impaired induction of the heme oxygenase 1 (HO-1)/carbon monoxide (CO) pathway downstream to the PI3K/AKT signaling cascade. Activation of this pathway in response to infection protects the tissues by inducing anti-oxidant, anti-inflammatory, anti-apoptotic and antibactericidal cellular responses. We are investigating the therapeutic potential of modulating the HO-1/CO pathways as a new strategy for anti-inflammatory interventions in CF.This project is supported by CFF.

Hyper-inflammation, lung injury and remodeling in CF

Severe lung remodeling in CF mouse lungs after chronic exposure to LPS

Lung structural damage in CF is characterized by bronchial wall thickening, air trapping, and bronchiectasis. With the progression of CF disease, lung tissue remodeling becomes more prominent and irreversible, leading to a decline in lung function. The mechanisms causing progressive lung tissue remodeling in CF are unknown. We have developed a CF mouse model that recapitulates the non-resolving lung inflammation and the tissue remodeling observed in CF patients. Taking advantage of this mouse model, we are elucidating the role of monocyte and MΦs to the development of permanent structural lung disease in CF. Moreover, the studies are designed to assess the utility of targeting this pathway in the context of CF lung disease. This may help identify mechanism-based potential therapeutic targets that will prevent long-term lung tissue deterioration in patients with CF. This project is supported by CFF

CFTR modulators and monocyte/MΦs response to chronic lung inflammation

Human macrophages in murine lungs challenged with LPS (human CD68)

In collaboration with Drs. Helene, Krause, Flavell and Gallagher at The Yale Cooperative Center of Excellence in Hematology and Dr. Egan at the Yale CF Research Center we are developing models that will allow to study the CF immune system in mice and understand how CFTR-modulator therapy change the immune response in CF patients. The main goal of our study is to understand whether treatment with Trikafta, a newly approved triple combination therapy of CFTR modulators, directly affects the recruitment rate of CF affected monocytes to lung tissues in response to chronic inflammation in vivo. To this end, we will use a xenotransplant mouse model. These studies can provide unique information on how Trikafta treatment modulates the monocyte/MΦs response during chronic lung inflammation. This project is supported by CFF.