Am J Respir Crit Care Med. 2013 Jan 15;187(2):189-96. doi:10.1164/rccm.201208-1364OC. Epub 2012 Dec 6.

Cytotoxic Cells and Granulysin in Pulmonary Arterial Hypertension and Veno-Occlusive Disease.

Perros F, Cohen-Kaminsky S, Gambaryan N, Girerd B, Raymond N, Klingelschmitt I, Huertas A, Mercier O, Fadel E, Simonneau G, Humbert M, Dorfmüller P, Montani D.

Inserm U999, Faculté de médecine, Univ. Paris-Sud, Kremlin-Bicêtre, France.

Abstract

Rational: Pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease (PVOD) both display occlusive remodeling of the pulmonary vasculature responsible for increased pulmonary vascular resistances. Cytotoxic T-(CTL), Natural Killer-(NK) and Natural Killer T-(NKT) cells play a critical role in vascular remodeling in different physiological and pathological conditions. Granulysin (GNLY) represents a powerful effector protein for all these subpopulations.
OBJECTIVES: To analyze the cytolytic compartment of inflammatory cells in PAH and PVOD patients.
METHODS: The overall functional status of the cytolytic compartment was studied through epigenetic analysis of the GNLY gene in explanted lungs and in PBMC. Flow cytometry technology allowed analysis of specific circulating cytolytic cells and GNLY contents. A GNLY-specific ELISA allowed measurement of GNLY serum concentrations.
MEASUREMENTS AND MAIN RESULTS: A decrease in GNLY demethylation in the gDNA extracted from PBMC and explanted lungs was found specifically in PVOD but not in PAH. This was associated with a decrease in populations and subpopulations of CTL and NKT, and an increase of NK populations. Despite the reduced granulysin-containing cells in PVOD patients, GNLY serum levels were higher, suggesting these cells were wasting their content. Furthermore, the increase of GNLY concentration in the serum of PVOD was significantly higher than in PAH patients.
CONCLUSIONS: PVOD is characterized by alterations of circulating cytotoxic cell-subpopulations and by epigenetic dysregulation within the GNLY gene. Our findings may be helpful in the quest to develop needed diagnostic tools, including flow cytometry analyses, in order to screen for suspected PVOD in patients with pulmonary hypertension.

PMID:23220918