Pulmonary arterial hypertension (PAH) is a rare and incurable disease of the lung arteries that causes early death. In PAH, excess scar tissue and thickening of lung blood vessels occur as the results of increased cell “biomass.” These changes obstruct blood flow and are detrimental to the center, but until now the fundamental features of biomass in PAH weren’t known. A team led by investigators at Brigham and Women’s Hospital (BWH), a founding member of the Mass General Brigham healthcare system, in collaboration with Matthew Steinhauser, MD, a metabolism and cell imaging expert on the University of Pittsburg, and investigators on the University of Vienna, set out to higher understand the origins of arterial biomass in PAH.
Using an animal model of PAH, the team applied network medicine and advanced molecular imaging tools to discover chemical constructing blocks which are taken up by arterial cells and ultimately contribute to blood vessel obstruction. Using multi-isotope imaging mass spectrometry (MIMS) under the guidance of Steinhauser and Christelle Guillermier, PhD, at BWH, the researchers could pinpoint the situation and abundance of key contributors to biomass, including the amino acid proline and the sugar molecule glucose. Using MIMS, the team visualized proline and glucose tracers injected into the bloodstream of an animal model of PAH. They saw that the molecules were utilized by arterial cells of the lung to construct excess scar tissue (including the protein collagen), which contributed to blood vessel obstruction.
“Our study describes the world’s first use of multi-isotope imaging mass spectrometry (MIMS) within the study of lung disease,” said Bradley Wertheim, MD, of the Brigham’s Division of Pulmonary and Critical Medicine. “MIMS is a strong microscopy tool that produces a ‘molecular snapshot’ that may provide information right down to the resolution of a single cell.”
“These findings suggest that the uptake and metabolism of protein precursors could also be fundamental to PAH biology. Closer investigation of proline and glucose in human PAH may uncover opportunities to inhibit biomass formation, prevent obstruction of lung arteries, and reduce the prospect of heart failure for PAH patients,” said co-senior writer Bradley Maron, MD, of the Brigham’s Division of Cardiovascular Medicine.
Source:
Brigham and Women’s Hospital
Journal reference:
10.1172/jci.insight.163932