Overview

On Friday, September 12, 2025, the National Heart, Lung, and Blood Institute (NHLBI), of the National Institutes of Health (NIH), hosted a hybrid workshop titled “Lung Sensing and Its Implications in Diseases” in Bethesda, MD, and online. This event was open to the public. The workshop featured a keynote address, short scientific presentations, and discussions. Key workshop topics included cyclic GMP-AMP synthase (cGAS) in lung sensing, the lung–brain axis, lung sensing molecules and circuits, and lung sensing in disease. Participants included NHLBI and other federal staff members, academic researchers, and clinician–investigators. The videocast of the workshop can be found here: https://videocast.nih.gov/watch=57070

This workshop is relevant to following NHLBI’s strategic goals: 1) Understand Human Biology, 2) Reduce Human Disease, and 3) Advance Translational Research. It is responsive to NHLBI Strategic Vision Objectives 1-4.

Background

NHLBI hosted this workshop to consider and highlight the burgeoning understanding of the lung as not only a mechanical, respiratory organ but also as a sensory organ constantly exposed to extrinsic and intrinsic signals and stimuli. Afferent and efferent neurons and other cells throughout the airway play important roles in sensing and responding to biological, chemical, mechanical, and spatiotemporal cues (e.g., allergens, pathogens, toxins, water, acid, environmental stimuli, and the airway’s own mechanical environment). Lung cells must sense dynamic lung changes accurately and then respond appropriately to maintain homeostasis and healthy lung function. Failure, dysfunction, and maladaptive changes in the airway’s sensory capacity contribute to many diseases, such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis.

While much is known about how lung cells detect and respond to infectious agents, our understanding of how they sense non-pathogenic stimuli—such as gaseous molecules, volatile organic compounds, metabolites, nutrients, mechanical forces, spatial organization, and circadian rhythms—remains limited. Several critical questions remain unanswered: What types of molecules are involved in lung sensing, and what are their sources? Which cells are responsible for detecting these signals, and how do they do so? What are the downstream pathways and circuits that relay and respond to the signals? What are the consequences of disruptions in these sensing pathways? A systematic investigation into the physiological and pathological roles of lung sensing is essential to advance our understanding of lung health. Convening a dedicated workshop to identify current knowledge gaps, critical barriers, and emerging research opportunities is both necessary and timely. Insights from such a forum will help guide the development of innovative strategies to improve respiratory health.

Key Questions and Objectives

Which molecules, cells, and associated mechanisms contribute to lung sensing?

Which downstream circuits and pathways relay and respond to lung sensing signals?

What are the consequences of disruptions in these processes?

Overall Discussions

• The workshop reviewed the current understanding of how lung cells detect and respond to infectious agents.
• The workshop discussed the current understanding of how lung cells sense and respond to non-pathogenic stimuli such as gaseous molecules, volatile organic compounds, metabolites, nutrients, mechanical forces, spatial organization, and circadian rhythms.
• The workshop considered how lung cells sense and respond to lung changes to maintain homeostasis and how the failure to do so can contribute to disease.
• The workshop discussed knowledge gaps, future research opportunities, and challenges/barriers to advancing understanding of the physiological and pathological processes of lung sensing and improving lung health.

Key Opportunities and Gaps

• What are the mechanisms (e.g., Piezo, Hippo, and TRP) by which neurons and neuroendocrine cells in the lungs sense specific pathogens and release different neuropeptides to initiate an appropriate response (or by which commensal bacteria are ignored)? Is there a hierarchy to these mechanisms? Do sensory neurons or neuroendocrine cells undergo epigenetic changes after a pathogenic encounter that enable them to respond differently upon secondary encounters?
• What are the specific channels or molecules that mediate sensing of gases, lung volume, or irritants in the lung? How can novel multi-omics technologies (e.g., genomics, transcriptomics, proteomics, metabolomics, and epigenomics) be used to discover new receptors and signaling pathways involved in inhaled pollutant detection in the lungs?
• How can studying spatial multi-omics along the proximal-distal axis of the airways and the vasculature improve the understanding of lung sensing?
• What are the AhR signaling pathways involved in pulmonary inflammation? How can we use this knowledge to develop preventative or therapeutic interventions?
• What is the role of HIF signaling in lung diseases (e.g., COPD and lung cancer) induced by inhaled environmental stressors?
• How do lung-innervating sensory neurons and their associated non-neuronal cells coordinate naturally occurring and clinically relevant physiological and pathological states of the lung? How do the activities and properties of lung sensing neurons and non-neuronal cells change during the progression and resolution of disease?
• Many diseases are initiated by wound healing, which results in aberrant proliferation of transient mucus-producing cells and a loss of the heterogeneity of cell  types needed for healthy lung performance. How much does loss of this diversity contribute to disease? How much of lung disease progression  stems from misrepair of tissue injury leading to fibrotic state?
• What new tools, models, and resources are needed to expand the understanding of lung sensing, to overcome the current limitations of animal models (e.g., neuropeptides differ widely across species, limiting the application of animal studies to human health)? Such tools, models and resources should enable investigators to overcome the technical limitations preventing capture of long-term neuronal activity, to create and optimize libraries of sensed compounds, and to implement more genetic and chemical sensor reagents.

Conclusion

Researchers have identified a spectrum of cell types in the airway that contribute to the lung’s capacity to sense and respond to gases, chemicals, and other stimuli, including allergens, viruses, bacteria, pollutants, toxins, and mechanical forces acting on the airway. Sensory function enables the lung to sense dynamic changes and respond appropriately to maintain homeostasis. Disruptions in the airway’s sensory capacity can cause, exacerbate, or lead to diseases and chronic respiratory conditions.

Investigators have begun to characterize cell types, associated mechanisms, and the pathways and circuits through which the airway interfaces with the nervous system (i.e., the lung–brain axis). Pathways characterized to date and discussed during the workshop include: (1) viral DNA binding to the cGAS enzyme and initiating immune responses; (2) Piezo, TRPV, and other channels involved in sensory processes like sensing mechanical forces in the lung; and (3) lung sensing processes initiated by acid, hyperoxia/hypoxia, viruses, bacteria, environmental exposures, irritants, diet, metabolism, and other endogenous triggers.

Many respiratory diseases and other health conditions—including asthma, cystic fibrosis, COPD, viral infections, allergies, and sleep disordered breathing (e.g., sleep apnea)—are affected by disruptions to lung sensing. Further, adaptive and maladaptive responses to mechanical feedback and associated inflammation can exacerbate the dysregulation of lung sensing, leading to elevated damage and inflammation. A more complete understanding of lung sensing and its involvement in human health may lead to the development of new medical interventions to improve lung health and function.

Publication Plan

The meeting participants are developing a workshop report, outlining the meeting’s main objectives, knowledge gaps, and future research opportunities that were identified at the workshop, for publication in a peer-reviewed journal.

Workshop Participants

Chairs

• Y. S. Prakash, Mayo Clinic, Rochester, Minnesota, USA.
• Xin Sun, University of California, San Diego, La Jolla, California, USA.

Speakers, Moderators, and Designated Writers

• Zhijian Chen, University of Texas Southwestern, Dallas, Texas.
• Matthew Drake, Oregon Health and Science University, Portland, Oregon, USA.
• Adam L Haber, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA.
• Nicholas Jendzjowsky, The Lundquist Institute for Biomedical Innovation at Harbor-University of California, Los Angeles, Torrance, California, USA.
• Maya Kotas, University of California, San Francisco, San Francisco, California, USA.
• Christin S. Kuo, Stanford University School of Medicine, Stanford, California, USA.
• Peng Li, University of Michigan, Ann Arbor, Michigan, USA.
• Yin Liu, HHMI/Janelia Research Campus, Ashburn, Virginia, USA.
• Gary Mouradian, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
• Alexandra Noël, Louisiana State University, Baton Rouge, Louisianna, USA.
• Christina Pabelick, Mayo Clinic, Rochester, Minnesota, USA.
• Sara Prescott, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA.
• Jay Rajagopal, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA.
• Leah R. Reznikov, University of Florida, Gainesville, Florida, USA.
• Jody Rosenblatt, King's College London, London, UK.
• Laura Seeholzer, Stanford University, Stanford, California, USA.
• Yujuan Su, University of California, San Diego, La Jolla, California, USA.
• Thomas E Taylor-Clark, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.
• Daniel J Tschumperlin, Mayo Clinic, Rochester, Minnesota, USA.

NHLBI Staff

• Gustavo Matute-Bello, Acting Director, Division of Lung Diseases, NHLBI.
• Christian R. Gomez, Program Director, Division of Lung Diseases, NHLBI.
• Sara Lin, Program Director, Division of Lung Diseases, NHLBI.
• Qing Lu, Program Director, Division of Lung Diseases, NHLBI.
• Emmauel Mongodin, Program Director, Division of Lung Diseases, NHLBI.
• Louis Vuga, Program Director, Division of Lung Diseases, NHLBI.
• Guofei Zhou, Chief, Acute and Infectious Lung Diseases Branch, Division of Lung Diseases, NHLBI.

Disclaimer: The findings, knowledge gaps, and opportunities described here represent a summary of individual opinions and ideas expressed during the workshop. The summary does not represent a consensus opinion or directive made to or by NHLBI or the NIH.

Agenda

For further information about the workshop, please see the event agenda.