Heparanase Activates Pulmonary Fibroblasts During Idiopathic Pulmonary Fibrosis
Abstract
Fiscal Year 2016 Peer Reviewed Medical Research Program Topic Area: Pulmonary Fibrosis. The lungs, being in continuous contact with the atmosphere, are repeatedly exposed to airborne irritants. Military Service members face heightened risks of such exposure. While the lung is typically resistant to damage, occasionally airborne irritants can be sufficiently toxic to trigger the sudden onset of ?acute lung injury,? a critical illness with a high risk of death, yet potential for lung recovery in survivors. Alternatively, lung injury can be slowly developing, leading to relentless, irreversible lung scarring (?pulmonary fibrosis?) that is progressively disabling and ultimately fatal. To simplify the study of these highly complex diseases, lung injury researchers typically separate themselves into specialists focusing on acute (and resolving) lung injury or specialists focusing on progressive, unremitting injury. This scientific separation risks neglecting important acute lung injury advances that could help patients exposed to lung irritants that cause progressive lung fibrosis. Heparan sulfate is one such known contributor to acute lung injury that has yet to be studied in chronic lung fibrosis. Heparan sulfate is a sugar chain that controls a number of vital lung functions. Accordingly, recent studies have identified that degradation of heparan sulfate is an important cause of acute lung injury. Heparanase-blocking drugs, therefore, may help patients with this severe critical illness. We have now discovered that heparan sulfate degradation may also occur in patients with chronic, progressive scarring. The role of ongoing heparan sulfate degradation as a cause of pulmonary fibrosis, however, is unexplored. In this proposal, we seek to apply lessons learned from the study of acute lung injury to the study of chronic lung scarring. Specifically, we will study how a heparan sulfate-degrading enzyme (?heparanase?) can trigger normal lungs to abnormally (and persistently) produce scar, leading to pulmonary fibrosis. We will study this by: (1) Detecting the presence of heparanase in lung biopsies from patients with pulmonary fibrosis, and determining if sicker patients have more heparanase. (2) Exposing lung cells (isolated from normal lungs) to heparanase, and determining if these cells begin to behave like lung cells isolated from patients with pulmonary fibrosis. (3) Blocking heparanase in mice, and determining if these mice are protected from the development of lung fibrosis. This study may identify new treatments options that can protect military Service members and civilians exposed to airborne toxins from developing chronic lung disease, such as pulmonary fibrosis.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710051
Entities
People
- Yimu Yang
Organizations
- United States Army
- University of Colorado Denver