Erica Herzog, MD, PhD

My training as a physician scientist motivates me to seek new treatments for chronic lung diseases. I have spent more than 15 years pursuing this goal by studying the relationship mechanisms of fibrotic remodeling in the adult mammalian lung. My laboratory has had a sustained impact on the field of pulmonary fibrosis and is credited with several seminal discoveries that have been verified and reproduced in laboratories around the world. My early work helped ignite interest in role of innate immunity in lung injury, repair, and remodeling. We are also credited with providing new insight into the convergent and divergent mechanisms existing at the interface of lung injury and repair. More recent work focuses on how neuronal guidance proteins are involved in these processes, and in modeling the biophysical attributes of the normal and diseased adult lung. I am committed to training the next generation of Respiratory Scientists and in my close to 20 years at Yale have mentored numerous individuals at all stages of training and am currently accepting predoctoral students from YSM and GSAS.

1. Role of the immune system in lung injury, repair, and remodeling. When I embarked upon my PhD during Pulmonary fellowship in 2001, pulmonary fibrosis was viewed as lacking an immunopathogenic component. My graduate work, however, determined that the recruitment and activation of bone marrow derived cells impacts injury, repair, and remodeling via paracrine orchestration of stromal responses. In fact, it was work from my lab, among others, that revitalized interest in how immunity orchestrates fibrotic injury and repair in the adult mammalian lung. We showed that the accumulation of innate immune cells such as macrophages or an ECM producing population of cells called fibrocytes could amplify critical events in fibrogenesis including TGFb1 activation, ECM production, and myofibroblast transformation; that that immune events in the lung could be monitored in the peripheral blood in many forms of human pulmonary fibrosis. We ultimately found that because fibrocytes were rare and difficult to detect in the blood, removal or repolarizing of macrophages is a more viable therapeutic strategy for fibrotic lung disease. These studies have been replicated and expanded by labs around the world and contributed to the preclinical portfolio for the short pentraxin protein PRM151, which recently met its primary endpoint in a Phase II trial.

2. Convergent and divergent mechanisms of injury and repair. Our work has contributed to the growing recognition that cells of the innate immune system display a highly plastic and adaptable phenotype through which they differentially regulate injury and fibrotic remodeling. For example, using the 18-glycolsyl hydrolase protein Chi3L1 as a prototype, we were able to show that a single gene product can simultaneously suppress or promote injury and fibrosis depending on its temporospatial expression in the disease process. We have also shown that danger associated molecular pathogens released by cells exposed to apoptotic, soluble, and mechanical stimuli signal to adjacent cells to initiate a repair program. Importantly, these mediators can be detected in the tissue of patients with various forms of pulmonary fibrosis, cementing the association with human disease. Finally, in very recent work, we have collaborated with investigators in Yale’s School of Immunobiology to describe a new innate immune process by which the inflammation associated hormone GDF15 (also called macrophage inhibitory cytokine 1) controls systemic inflammation and tissue responses via central regulation of peripheral tolerance in multiple organs.

3. Role of Neuronal Guidance Proteins. In delineating the processes described above, we discovered an unexpected contribution of neuronal guidance proteins (NGPs) to IPF and related diseases. In performing these studies we initially focused on NGP function at the so called “immune synapse” through which immune cells communicate. However, as the work has evolved we have observed that NGP function might also relate to their originally described role as regulators of nerve migration and remodeling. Ongoing work in my lab seeks to re-evaluate lung injury, inflammation, pathologic remodeling and repair in the context of macrophage mediated adrenergic nerve remodeling in experimentally induced mammalian lung fibrosis and in IPF.

4. Modeling the Lung Microenvironment. In studying the immune responses described above, we observed that cells that were thought to be terminally differentiated could be reprogrammed by their microenvironment to adopt new functional characteristics. While such an event had been suspected for a while, it became exceedingly evident in our collaboration with Laura Niklason’s lab when cells seeded into a decellularized lungs homed to their geospatial niche, assumed appropriate function, and engendered a living, breathing organ. When we applied this method to fibrotic lungs we observed that the biochemical and biophysical attributes of the lung microenvironment influence the adherence, survival, apoptosis, proliferation, fate specification, and transformation of fibroblasts; and that crosstalk with macrophages influences these endpoints in both animal models and in humans with several forms of lung fibrosis. Our studies revealed a new form of bidirectional feedback between macrophages, fibroblasts, and microenvironmental factors in health and disease that heavily depends upon biophysical cues.