Date Published: January 1, 2018
Publisher: American Physiological Society
Author(s): Libang Yang, Jeremy Herrera, Adam Gilbertsen, Hong Xia, Karen Smith, Alexey Benyumov, Peter B. Bitterman, Craig A. Henke.
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.
Idiopathic pulmonary fibrosis (IPF) progresses in a stereotypic manner. The disease begins in the peripheral basilar portions of the lungs (19, 28, 29). This nonrandom peripheral-basilar distribution of fibrosis gives rise to a chest computed tomography scan pattern now considered diagnostic for IPF (28). As the disease progresses, fibrosis spreads centrally in an axial distribution producing the distinct anatomical pattern designated usual interstitial pneumonia (27). 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).
The mechanisms underlying the relentless progression of fibrosis in IPF remain incompletely understood. We previously identified pathological MPCs as a source of the activated myofibroblasts mediating fibrotic destruction in IPF (40, 42). The concept that fibrotic progression is driven by a fibrogenic MPC has fundamental implications for fibrosis biology and treatment. This work represents a paradigm shift directing IPF experimental therapeutics toward a specific, fibrogenic progenitor cell (sub)population rather that the activated myofibroblast population as a whole; analogous to what has occurred in cancer biology with the discovery of cancer stem cells/tumor-initiating cells as the cells that must be targeted to achieve a cure. Nevertheless, despite this discovery, the mechanisms governing IPF MPC fibrogenicity are incompletely defined. In this report, we show that IPF MPCs and their progeny secrete markedly increased amounts of IL-8 compared with control cells, which can function in an autocrine and paracrine manner to increase IPF mesenchymal cell population size, motility, and macrophage recruitment.
This work was supported by National Heart, Lung, and Blood Institute Grants R01-HL-125227 (to C. A. Henke) and R01-HL-125236 (to P.B. Bitterman) and funds provided by the Witowski and O’Brien families.
No conflicts of interest, financial or otherwise, are declared by the authors.
L.Y. and C.A.H. conceived and designed research; L.Y., J.H., A.J.G., H.X., K.S., and A.B. performed experiments; L.Y., J.H., A.J.G., H.X., K.S., and A.B. analyzed data; L.Y., J.H., A.J.G., H.X., K.S., A.B., and C.A.H. interpreted results of experiments; L.Y. prepared figures; L.Y., P.B.B., and C.A.H. drafted manuscript; L.Y., J.H., A.J.G., H.X., K.S., A.B., P.B.B., and C.A.H. edited and revised manuscript; L.Y., J.H., A.J.G., H.X., K.S., A.B., P.B.B., and C.A.H. approved final version of manuscript.