Protection and Recovery from Burn-Associated Inhalation Injury Through Pharmacologic Manipulation of an Endogenous Airway Regenerative Pathway
Abstract
The mammalian respiratory system supplies oxygen for the entire organism by employing millions of gas exchange units, the alveoli. The thin-walled structure of these delicate epithelial sacs ensures a minimal barrier that facilitates adequate gas exchange, but also renders them vulnerable to injury from inhaled particulates and toxins, such as the smoke and other by-products of fires, including military burn pits, or from the military use of chemical weapons and other explosive devices. To minimize such exposure, the airway tree is critically important for the protective functions of trapping and clearing injurious agents before they reach the alveoli. In this protective role the airway employs a mucociliary clearance system to absorb and remove toxic gases and particulates. Should the airway epithelium itself be injured as it engages harmful agents, it can mount a vigorous regenerative program by activating airway stem cell proliferation and differentiation. Among the most common airway pathologies are those associated with acute injury from inhalation of external toxicants. The rationale of our proposal is based on the discovery of an epithelial-mesenchymal feedback (EMF) circuit that plays a critical and beneficial role in airway response to acute inhalation injury. EMF circuit activity regulates regenerative activity in many adult organs and is generally initiated by epithelial expression of one of the three members of the Hedgehog family of signaling proteins. Response to this epithelial Hedgehog signal occurs in the underlying mesenchyme, and generally includes expression of secreted signals that feed back to the epithelium and regulate activities such as proliferation and differentiation. The airway EMF circuit is characterized by several unique features: First, the epithelial signal is Desert hedgehog, the least-studied member of the Hedgehog family but functionally the most important in adult airway. Second, in airway Desert hedgehog expression is confined to rare pulmonary neuroendocrine cells (PNECs), which comprise <1% of the cells of the epithelium. Third, the mesenchymal signal elicited by Desert hedgehog via its target transcription factor GLI1 is interleukin-6 (IL-6), which feeds back to trigger a response throughout the entire airway mucosa. In our preliminary studies we have observed that genetic or pharmacologic disruption of the airway EMF circuit compromises the response to inhalation injury in mice exposed acutely to SO2 gas, a common environmental toxicant used to model acute inhalation injury. Following this injury, these mice with diminished EMF circuit activity display airway damage augmented by increased apoptotic loss of epithelial cells and attenuated proliferation of basal epithelial stem or progenitor cells; these initial acute effects are accompanied by a significant longer-term delay in airway regeneration. Pharmacologic activation of the airway EMF circuit in contrast protects the airway epithelium from cell loss, suggesting a novel therapeutic approach to acute inhalation injury. Our objective is to determine the mechanism of EMF activation (Aim 1), to explore therapeutic modulation of EMF activity in inhalation injury (Aim 2), and to verify that, as in mice, an airway EMF circuit protects and stimulates regeneration of the human airway (Aim 3). Successful completion of these studies will elucidate the function of this airway regenerative regulatory circuit and will provide the basis for development of pharmacologic intervention(s) to improve prophylactic and post-injury management of actual or anticipated inhalation injures from burn related complications, or inhalation of toxic gas in the military setting, in this way directly benefiting injured active Service Members, and Veterans. These benefits can also extend to the public in addressing inhalation injuries from urban fires, and volcanic eruptions, and wildfires, which are occurring with increasing frequency and i
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310923
Entities
People
- Philip A Beachy
Organizations
- Stanford University
- United States Army