LINKS: Pulmonary Arterial Hypertension Bronchiolitis Obliterans Syndrome Chemical Lung Injury

Pulmonary Arterial Hypertension – A Rare Disease with a High Mortality Rate 

Over 50,000 people have been diagnosed with PAH (WHO Group 1) in the US1 and this disease is almost twice as common in women than men.2 PAH is a rapidly progressive disease with an approximate 50% five-year mortality rate.3 The disease is characterized by vascular remodeling in the pulmonary arterial bed. This pathology leads to decreased vessel elasticity, increased arterial blood and resistance in the lungs, and an increased workload for the heart. Individuals with PAH typically succumb to right ventricular heart failure.

Pulmonary Arteriole

pulmonary arteriole

PAH is currently treated with vasodilators, which offer some benefit but fail to address the underlying vessel remodeling believed to be responsible for the disease’s high morbidity and mortality rates. Reducing peripheral serotonin production is a novel approach for the treatment of PAH and has the potential to halt or reverse pulmonary remodeling. Rodatristat is being developed as an adjunctive treatment for PAH as our research indicate that its mechanism of action is additive to the effects of standard of care.

Pulmonary Vasculature Remodels as PAH Progresses10

Pulmonary Vasculature Remodels as PAH Progresses

Bronchiolitis Obliterans Syndrome (BOS) 

Immunosuppression therapy after lung transplantation is often inadequate at preventing bronchiolitis obliterans syndrome (BOS), a life-threatening form of chronic lung allograft dysfunction (CLAD).  Registry data from the International Society of Heart and Lung Transplantation (ISHLT) reports a median BOS-free survival of only ~3.2 and ~3.8 years for recipients of unilateral and bilateral lung transplants, respectively; with overall 5-year survival rates at 55.8% and 66.2%12.

BOS is driven by inadequate suppression of cytotoxic mediators, following for example an infection, that leads to prolonged upregulation of various inflammatory cytokines and chemokines that promote inflammatory cell infiltration into the transplanted lung 13, 14, 15. This inflammatory process leads to recruitment of fibroblasts and myofibroblasts with resulting deposition of airway subepithelial extracellular matrix and fibrosis of non-cartilaginous smaller airways (membranous and respiratory bronchioles). This fibrosis leads to the characteristic luminal obstruction or total occlusion of BOS. 

Other predisposing conditions for BOS include: allogeneic hematopoietic stem cell transplantation (HSCT) which develops in 4-6% of patients likely as a form of chronic graft versus host disease (cGVHD)16, pulmonary complications of rheumatologic diseases (e.g. rheumatoid arthritis and scleroderma), noxious irritant gas inhalation (e.g. chlorine and ammonia) and food flavoring chemical dust inhalation (diacetyl). 

BOS is considered an irreversible condition with poor responses reported for the limited  treatment options available. Current therapies may reduce the decline in pulmonary function, but are not expected to halt or reverse the progression of BOS.

Bronchiolar wall thickened by inflammatory fibrosis (Barker AF, et al. (2014). Obliterative Bronchiolitis. NEJM. 370:1820-8)

More detailed information on BOS can be found on the Lung Transplant Foundation website.

Chemical Lung Injury 

Chemical lung injuries can result from the inhalation of noxious or irritant chemical gases (e.g. sulfur mustard, chlorine, ammonia or components of vaping products) as well as other toxicants such as smoke and particulates. These injuries may be a result of intentional or accidental exposure and may result in life-long disability or possibly death.

Exposure to noxious agents has been associated with upregulation of IL-1 and other inflammatory mediators. Upregulation of these inflammatory agents may drive additional damage beyond that caused directly by the chemical agent such as fibrosis in the subepithelial tissues and smaller bronchioles. Unchecked, this fibrosis leads to scarring or occlusion of the bronchioles impairing oxygen uptake and increasing the risk of mortality.

1. Datamonitor Pulmonary Hypertension Disease Coverage   2. Prins KW and Thenappan T. Cardiol Clin 2016   3. Thenappan T. BMJ 2018   4. Raghu G. European Respiratory Journal 2016   5. Leslie KO. Arch Pathol Lab Med 2012   6. Criado E. Radiographics 2010   7. Spagnolo P et al. Lancet Resp Med 2018   8. Shlobin OA and Nathan SD. Eur Respir J 2012   9. Kirkil G et al. Chest 2017 10. 11. National Heart, Lung and Blood Institute 12. Kulkarni, H.S., et al., Bronchiolitis obliterans syndrome-free survival after lung transplantation: An International Society for Heart and Lung Transplantation Thoracic Transplant Registry analysis. J Heart Lung Transplant, 2019. 38(1): p. 5-16. 13. Belperio, J.A., et al., Critical role for CXCR3 chemokine biology in the pathogenesis of bronchiolitis obliterans syndrome. J Immunol, 2002. 169(2): p. 1037-49. 14. Shino, M.Y., et al., CXCR3 ligands are associated with the continuum of diffuse alveolar damage to chronic lung allograft dysfunction. Am J Respir Crit Care Med, 2013. 188(9): p. 1117-25. 15. Hodge G., et al. BOS Is Associated With Increased Cytotoxic Proinflammatory CD8 T, NKT-Like, and NK Cells in the Small Airways. Transplantation 2017 Oct;101(10):2469-2476. 16. Dudek, A.Z., et al., Bronchiolitis obliterans in chronic graft-versus-host disease: analysis of risk factors and treatment outcomes. Biol Blood Marrow Transplant, 2003. 9(10): p. 657-66.