Dataset Information

Human Neutrophils in Pulmonary Arterial Hypertension by LC-MSMS

ABSTRACT: Neutrophil elastase (NE) is implicated in pulmonary arterial hypertension (PAH) but the role of neutrophils in the pathogenesis of PAH is unclear. Here we show that neutrophils from PAH vs. control subjects produce and release increased NE associated with enhanced extracellular trap formation. PAH neutrophils are highly adherent and show decreased migration consistent with increased vinculin, identified on proteomic analysis and previously linked to an antiviral response. This was substantiated by a transcriptomic interferon signature in PAH neutrophils and an increase in human endogenous retrovirus (HERV-K) envelope protein. NE and interferon genes are induced by HERV-K envelope and vinculin is increased by HERV-K dUTPase that is elevated in PAH plasma. Neutrophil exosomes from PAH plasma contain increased NE and HERV-K envelope and induce pulmonary hypertension in mice, that is mitigated by the NE inhibitor and antiviral agent, elafin. Thus elevated HERVs explain pathological neutrophils linked to PAH induction and progression.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Neutrophil

DISEASE(S): Pulmonary Hypertension

SUBMITTER: Shalina Taylor

LAB HEAD: Lihua Jiang

PROVIDER: PXD023134 | Pride | 2023-03-11

REPOSITORIES: Pride

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Publications

Endogenous Retroviral Elements Generate Pathologic Neutrophils in Pulmonary Arterial Hypertension.

Taylor Shalina S Isobe Sarasa S Cao Aiqin A Contrepois Kévin K Benayoun Bérénice A BA Jiang Lihua L Wang Lingli L Melemenidis Stavros S Ozen Mehmet O MO Otsuki Shoichiro S Shinohara Tsutomu T Sweatt Andrew J AJ Kaplan Jordan J Moonen Jan-Renier JR Marciano David P DP Gu Mingxia M Miyagawa Kazuya K Hayes Brandon B Sierra Raymond G RG Kupitz Christopher J CJ Del Rosario Patricia A PA Hsi Andrew A Thompson A A Roger AAR Ariza Maria E ME Demirci Utkan U Zamanian Roham T RT Haddad Francois F Nicolls Mark R MR Snyder Michael P MP Rabinovitch Marlene M

American journal of respiratory and critical care medicine 20221001 8

Rationale: The role of neutrophils and their extracellular vesicles (EVs) in the pathogenesis of pulmonary arterial hypertension is unclear. Objectives: To relate functional abnormalities in pulmonary arterial hypertension neutrophils and their EVs to mechanisms uncovered by proteomic and transcriptomic profiling. Methods: Production of elastase, release of extracellular traps, adhesion, and migration were assessed in neutrophils from patients with pulmonary arterial hyperte ...[more]

PMID: 35696338

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Project description:Although the accumulation of neutrophils in the lungs and airways is common to many inflammatory lung diseases, including acute lung injury, the alterations that neutrophils undergo as they leave the peripheral circulation and migrate into the lungs have not been well characterized. Human volunteers were exposed to endotoxin by bronchoscopic instillation. The resulting air space neutrophil accumulation and peripheral blood neutrophils were isolated 16 h later, compared with circulating neutrophils isolated before or after to the pulmonary endotoxin exposure, and compared with circulating neutrophils exposed to endotoxin in vitro. Microarray analysis was performed on air space, circulatory, and in vitro endotoxin-stimulated neutrophils. Functional analysis included the determination of neutrophil apoptosis, chemotaxis, release of cytokines and growth factors, and superoxide anion release. Dramatic gene expression differences were apparent between air space and circulating neutrophils: approximately 15% of expressed genes have altered expression levels, including broad increases in inflammatory- and chemotaxis-related genes, as well as antiapoptotic and IKK-activating pathways. Functional analysis of air space compared with circulating neutrophils showed increased superoxide release, diminished apoptosis, decreased IL-8-induced chemotaxis, and a pattern of IL-8, macrophage inflammatory protein-1beta, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha release different from either unstimulated or LPS-stimulated circulating neutrophils. Many of these changes are not elicited by in vitro treatment with endotoxin. Limited differences were detected between circulating neutrophils isolated before and 16 h after pulmonary endotoxin instillation. These results suggest that neutrophils sequestered in the lung become fundamentally different from those resident in the circulation, and this difference is distinct from in vitro activation with endotoxin.

Dataset Information

Human Neutrophils in Pulmonary Arterial Hypertension by LC-MSMS

Publications

Endogenous Retroviral Elements Generate Pathologic Neutrophils in Pulmonary Arterial Hypertension.

Similar Datasets

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