The Role of Fibrocytes in Sickle Cell Lung Disease

Joshua J Field,Ling Liu,Borna Mehrad,Brett A Strieter,Joel Linden,Marie D Burdick,Michael R Debaun,Robert M Strieter,C Edward Rose,Neeraj Vij

doi:10.1371/journal.pone.0033702

Abstract

BackgroundInterstitial lung disease is a frequent complication in sickle cell disease and is characterized by vascular remodeling and interstitial fibrosis. Bone marrow-derived fibrocytes have been shown to contribute to the pathogenesis of other interstitial lung diseases. The goal of this study was to define the contribution of fibrocytes to the pathogenesis of sickle cell lung disease.Methodology/Principal FindingsFibrocytes were quantified and characterized in subjects with sickle cell disease or healthy controls, and in a model of sickle cell disease, the NY1DD mouse. The role of the chemokine ligand CXCL12 in trafficking of fibrocytes and phenotype of lung disease was examined in the animal model. We found elevated concentration of activated fibrocytes in the peripheral blood of subjects with sickle cell disease, which increased further during vaso-occlusive crises. There was a similar elevations in the numbers and activation phenotype of fibrocytes in the bone marrow, blood, and lungs of the NY1DD mouse, both at baseline and under conditions of hypoxia/re-oxygenation. In both subjects with sickle cell disease and the mouse model, fibrocytes expressed a hierarchy of chemokine receptors, with CXCR4 expressed on most fibrocytes, and CCR2 and CCR7 expressed on a smaller subset of cells. Depletion of the CXCR4 ligand, CXCL12, in the mouse model resulted in a marked reduction of fibrocyte trafficking into the lungs, reduced lung collagen content and improved lung compliance and histology.ConclusionsThese data support the notion that activated fibrocytes play a significant role in the pathogenesis of sickle cell lung disease.

Highlights

Sickle cell disease (SCD) is the most common monogenic inherited disorder in African-Americans [1]
These data support the notion that activated fibrocytes play a significant role in the pathogenesis of sickle cell lung disease
Since previous studies had demonstrated that elevated fibrocytes can be found in the circulation of patients with interstitial lung disease (ILD) [23,25], we wanted to determine whether fibrocytes were present in patients with SCD under similar conditions

Summary

Introduction

Sickle cell disease (SCD) is the most common monogenic inherited disorder in African-Americans [1]. The two most common complications of SCD, vaso-occlusive pain crises (VOC) and acute chest syndrome (ACS), are the major risk factors for the development of interstitial lung disease (ILD) [2], a risk for morbidity and mortality in patients with SCD [2,3]. While many adults with SCD do not exhibit all features of SCLD, a restrictive pattern on pulmonary function tests is the most consistent clinical feature; for example, 74% of adults in a large prospective cohort study SCD had restrictive lung disease [6]. These studies underscore the need to better understand the pathogenesis of ILD in patients with SCD. The goal of this study was to define the contribution of fibrocytes to the pathogenesis of sickle cell lung disease

Objectives

Methods

Results

Conclusion