Treprostinil inhibits the recruitment of bone marrow-derived circulating fibrocytes in chronic hypoxic pulmonary hypertension

Abstract

A unique subpopulation of peripheral blood mononuclear cells that exhibit a parallel expression of haematopoietic and mesenchymal markers has been described as ''circulating fibrocytes''. These cells were demonstrated to obtain a fibroblastic phenotype in tissues or cell culture and contribute to pulmonary fibrotic disorders and tissue remodelling processes.The aim of our study was to characterise the recruitment of circulating fibrocytes in vivo in the model of chronic hypoxic pulmonary hypertension in mice and to analyse the therapeutic effect of the stable prostacyclin analogue trepostinil with respect to this cell population.To track circulating fibrocytes in vivo, we transplanted wild-type mice with bone marrow from ubiquitously eGFP expressing mice and subjected them to chronic hypoxia. We observed significantly increased recruitment of circulating fibrocytes to the remodelled pulmonary resistance arteries in response to hypoxia. Treatment with treprostinil significantly reduced the recruitment of these cells compared to normoxic mice. Treprostinil also reduced right ventricular systolic pressure and slightly reduced the vascular remodelling but failed to reverse the right ventricular hypertrophy.In summary, we show that circulating fibrocytes contribute to hypoxic pulmonary vascular remodelling and may be specifically targeted by a prostacyclin analogue. Further investigations of cellular and paracrine mechanisms are warranted to decipher their role in pulmonary hypertension.

Circulating fibrocytes and pulmonary arterial hypertension: Figure 1–

“…1g). In accordance with NIKAM et al [2], who found rare fibrocytes in only two cases out of 10, both with plexiform lesions, we did not observe fibrocyte accumulation (i.e. cells expressing both CD45 and vimentin) in the perivascular areas of remodelled small pulmonary arteries in the PAH lungs of four samples we analysed (data not shown).…”

“…Another nonexclusive hypothesis is that the low level of circulating fibrocytes is due to their increased pulmonary vascular recruitment. This hypothesis, raised by FRID et al [5], is not consistent with data obtained in PAH lungs here and by others [2] describing normal fibrocyte cell count in the perivascular areas of small pulmonary arteries. Furthermore, it remains difficult to extrapolate from studies in the hypoxic model of PAH to the human disease, in which lungs are examined at the pulmonary transplantation time-point, after long disease duration.…”

“…We read with great interest the recent editorial by STENMARK et al [1] about the potential role of fibrocytes in pulmonary arterial hypertension (PAH) and the original article by NIKAM et al [2] showing the contribution of bone marrow-derived circulating fibrocytes to hypoxic vascular remodelling and inhibition of their recruitment by treprostinil. Many recent reports indicate a contribution of endothelial and haematopoietic progenitor cells [3], attracted via the CXC chemokine ligand 12/CXC chemokine receptor (CXCR)4 axis in the lung [4], but the role of fibrocytes in PAH is still not clear.…”

“…The use of positive end-expiratory pressure (PEEP) and NPPV often results in the successful treatment of COPD patients with respiratory distress [1,2]. If, despite maximal medical management, respiratory distress and gas exchange deteriorate with increasing tachypnoea and acidosis, and with altered level of consciousness, then tracheal intubation and mechanical…”

Fibrocytes: potential new therapeutic targets for pulmonary hypertension?

“…The study of NIKAM et al [31] in the current issue of the European Respiratory Journal provides further support that fibrocytes accumulate in the pulmonary arteries of animals with chronic hypoxic pulmonary hypertension. This work builds on previous studies demonstrating that, in both a large animal model (neonatal calf) and hypoxic rats and mice, fibrocytes accumulate in the perivascular lesions of the vessel wall under chronically hypoxic conditions [29,32].…”