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Single-Cell Imaging Maps Inflammatory Cell Subsets to Pulmonary Arterial Hypertension Vasculopathy.
Ferrian, Selena; Cao, Aiqin; McCaffrey, Erin F; Saito, Toshie; Greenwald, Noah F; Nicolls, Mark R; Bruce, Trevor; Zamanian, Roham T; Del Rosario, Patricia; Rabinovitch, Marlene; Angelo, Michael.
Afiliação
  • Ferrian S; Department of Pathology.
  • Cao A; Early Clinical Development Informatics, Genentech Inc., South San Francisco, California.
  • McCaffrey EF; Department of Pediatrics.
  • Saito T; Vera Moulton Wall Center for Pulmonary Vascular Disease.
  • Greenwald NF; Cardiovascular Institute, and.
  • Nicolls MR; Basic Science and Engineering (BASE) Initiative, Betty Irene Moore Children's Heart Center, Stanford, California.
  • Bruce T; Department of Pathology.
  • Zamanian RT; Department of Pediatrics.
  • Del Rosario P; Department of Pathology.
  • Rabinovitch M; Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California.
  • Angelo M; Veterans Affairs Palo Alto Health Care System, Palo Alto, California.
Am J Respir Crit Care Med ; 209(2): 206-218, 2024 Jan 15.
Article em En | MEDLINE | ID: mdl-37934691
ABSTRACT
Rationale Unraveling immune-driven vascular pathology in pulmonary arterial hypertension (PAH) requires a comprehensive understanding of the immune cell landscape. Although patients with hereditary (H)PAH and bone morphogenetic protein receptor type 2 (BMPR2) mutations have more severe pulmonary vascular pathology, it is not known whether this is related to specific immune cell subsets.

Objectives:

This study aims to elucidate immune-driven vascular pathology by identifying immune cell subtypes linked to severity of pulmonary arterial lesions in PAH.

Methods:

We used cutting-edge multiplexed ion beam imaging by time of flight to compare pulmonary arteries (PAs) and adjacent tissue in PAH lungs (idiopathic [I]PAH and HPAH) with unused donor lungs, as controls. Measurements and Main

Results:

We quantified immune cells' proximity and abundance, focusing on those features linked to vascular pathology, and evaluated their impact on pulmonary arterial smooth muscle cells (SMCs) and endothelial cells. Distinct immune infiltration patterns emerged between PAH subtypes, with intramural involvement independently linked to PA occlusive changes. Notably, we identified monocyte-derived dendritic cells within PA subendothelial and adventitial regions, influencing vascular remodeling by promoting SMC proliferation and suppressing endothelial gene expression across PAH subtypes. In patients with HPAH, pronounced immune dysregulation encircled PA walls, characterized by heightened perivascular inflammation involving T cell immunoglobulin and mucin domain-3 (TIM-3)+ T cells. This correlated with an expanded DC subset expressing indoleamine 2,3-dioxygenase 1, TIM-3, and SAM and HD domain-containing deoxynucleoside triphosphate triphosphohydrolase 1, alongside increased neutrophils, SMCs, and alpha-smooth muscle actin (ACTA2)+ endothelial cells, reinforcing the heightened severity of pulmonary vascular lesions.

Conclusions:

This study presents the first architectural map of PAH lungs, connecting immune subsets not only with specific PA lesions but also with heightened severity in HPAH compared with IPAH. Our findings emphasize the therapeutic potential of targeting monocyte-derived dendritic cells, neutrophils, cellular interactions, and immune responses to alleviate severe vascular pathology in IPAH and HPAH.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Hipertensão Arterial Pulmonar / Hidralazina / Hipertensão Pulmonar Limite: Humans Idioma: En Revista: Am J Respir Crit Care Med Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Hipertensão Arterial Pulmonar / Hidralazina / Hipertensão Pulmonar Limite: Humans Idioma: En Revista: Am J Respir Crit Care Med Ano de publicação: 2024 Tipo de documento: Article