IL-8 mediates idiopathic pulmonary fibrosis mesenchymal progenitor cell fibrogenicity

Libang Yang,Peter B Bitterman,Hong Xia,Karen Smith,Craig A Henke,Adam Gilbertsen,Jeremy Herrera,Alexey Benyumov

doi:10.1152/ajplung.00200.2017

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease, but the mechanisms driving progression remain incompletely defined. We previously reported that the IPF lung harbors fibrogenic mesenchymal progenitor cells (MPCs), which serve as a cell of origin for IPF fibroblasts. Proliferating IPF MPCs are located at the periphery of fibroblastic foci in an active cellular front at the interface between the myofibroblast-rich focus core and adjacent normal alveolar structures. Among a large set of genes that distinguish IPF MPCs from their control counterparts, we identified IL-8 as a candidate mediator of IPF MPC fibrogenicity and driver of fibrotic progression. IPF MPCs and their progeny displayed increased steady-state levels of IL-8 and its cognate receptor CXCR1 and secreted more IL-8 than did controls. IL-8 functioned in an autocrine manner promoting IPF MPC self-renewal and the proliferation and motility of IPF MPC progeny. Secreted IL-8 also functioned in a paracrine manner stimulating macrophage migration. Analysis of IPF lung tissue demonstrated codistribution of IPF MPCs with activated macrophages in the active cellular front of the fibroblastic focus. These findings indicate that IPF MPC-derived IL-8 is capable of expanding the mesenchymal cell population and recruiting activated macrophages cells to actively evolving fibrotic lesions.

Highlights

IntroductionThe disease begins in the peripheral basilar portions of the lungs [19, 28, 29]
Idiopathic pulmonary fibrosis (IPF) progresses in a stereotypic manner
It is important to note that we found markedly higher levels of IL-8 in IPF MPC progeny compared with IPF MPCs

Summary

Introduction

The disease begins in the peripheral basilar portions of the lungs [19, 28, 29] This nonrandom peripheralbasilar distribution of fibrosis gives rise to a chest computed tomography scan pattern considered diagnostic for IPF [28]. Fibroblastic foci, the signature morphologic lesions of IPF, are frequently found at the leading edge of fibrosis [10, 16, 17, 23, 27]. They vary greatly in size, ranging from small discrete lesions to large serpiginous structures [16]. Our recent work suggests that there is temporal growth of fibroblastic foci as the lesions evolve due to local invasion of the fibrotic front into adjacent normal alveolar structures [42]

Methods

Results

Conclusion