Pulmonary fibrosis is the final common endpoint of a diverse group of diseases such as chronic hypersensitivity pneumonitis, silicosis, radiation injury, asbestosis, rheumatologic diseases, and idiopathic pulmonary fibrosis. To date there are no effective treatments to cure, stop or reverse the unremitting, fatal fibrosis. The role of the immune system has been repeatedly demonstrated to be intimately and indispensably linked to resolution of fibrosis. Indeed, our lab has robust published data demonstrating that vaccination with a vaccinia-based vaccine, after lung fibrosis has already been established, is effective at reversing established pathology as measured by decreased lung collagen deposition, histologic damage and improved lung function. Mechanistically vaccinia vaccination promotes resolution by inducing specific lung tissue resident memory T cells (Trm). Trm play an essential role in mediating protection against tissue specific challenges as well as greatly influence the tissue immune microenvironment. The mechanism by which the Trm regulate tissue specific pathology such as fibrosis is unknown. The completion of these studies will provide the insight and preclinical rationale for a novel paradigm shifting approach toward the treatment of lung fibrosis.

Team: Maureen Horton, Samuel Collins, Yee Chan-LI, Min-Hee Oh, Peter Illei, Jonathan Powell
Funding: R01 HL141490

The role of macrophages in promoting and preventing lung fibrosis is controversial and unclear. In the lungs, monocyte derived alveolar macrophages (MoAMs) are recruited from the bone marrow to respond to acute insults. Recently, MoAMs have also been shown to promote pathologic lung fibrosis. In contrast, Tissue Resident Alveolar Macrophages (TRAMs) (as their name implies) are local tissues macrophages that respond to lung insult and are believed to play a role in regulating inflammation and promoting tissue repair. In health, there is coordinated regulation of MoAMs (to fight infection) and TRAMs (to control inflammation and promote repair back to healthy lung tissue). We seek to provide fundamental and novel insight into the mechanisms promoting the generation and function of MoAMs and TRAMS within the lung

Team: Maureen Horton, Samuel Collins, Yee Chan-LI, Min-Hee Oh, Peter Illei, Jonathan Powell

Currently, there is no treatment to prevent, stop or reverse Acute Respiratory Distress Syndrome (ARDS) resulting a 20-50% mortality rate for its victims. The excess morbidity and mortality is not due to the initial insult, but rather to an excessive, unregulated inflammatory response in lieu of normal healing. It is becoming clear that metabolic programming plays a critical role in regulating immune and inflammatory responses. A critical component of the increased metabolism promoting inflammation is glutamine. Enhanced glutamine metabolism is critical for macrophage activation and M2 polarization and promotes fibroproliferation. We seek to attack this disease from a completely different perspective, that is, by approaching ARDS from a metabolic perspective. To this end, we hypothesize that inhibition of glutamine metabolism will promote accelerated resolution of ALI and prevent the development of ARDS by suppressing excessive cellular inflammation. Furthermore, by targeting glutamine metabolism to mitigate disease we seek to dissect the inflammatory and metabolic pathways that promote disease as well as those involved in promoting resolution. This represents a completely new approach for this deadly disease for which the only current treatment is supportive care.

Team: Maureen Horton, Samuel Collins, Yee Chan-LI, Min-Hee Oh, Roy Brower, Barbara SlusherJonathan Powell

The goal of this grant is to leverage our models of Acute Lung Injury and chronic Pulmonary fibrosis to define and dissect the role of metabolism in promoting these two pathological processes.  In addition, we will also test the hypothesis that targeting glutamine metabolism represents a novel means of arresting and reversing disease.  Furthermore, the data generated will identify novel (metabolic) pathways and consequently new potential therapeutic targets for treating acute and chronic inflammation.

Team: Maureen Horton, Samuel Collins, Yee Chan-LI, Min-Hee Oh, , Barbara Slusher,Jonathan Powell
Sponsor: Roche Pharmaceuticals

The goal of this clinical trial is to determine the efficacy of RVT-1601 (nebulizer cromolyn sodium) in the treatment of cough in patient with Idiopathic Pulmonary Fibrosis.

Team: Maureen Horton, Sarah Collins, Linda Breslin, Mark Liu
Sponsor: Respivant Sciences