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Idiopathic pulmonary fibrosis (IPF) is a poorly understood, progressive lethal lung disease with no known cure. In addition to alveolar epithelial cell (AEC) injury and excessive deposition of extracellular matrix proteins, chronic inflammation is a hallmark of IPF. Literature suggests that the persistent inflammation seen in IPF primarily consists of monocytes and macrophages. Recent work demonstrates that monocyte-derived alveolar macrophages (moAMs) drive lung fibrosis, but further characterization of critical moAM cell attributes is necessary. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is an important epidermal growth factor receptor ligand that has essential roles in angiogenesis, wound healing, keratinocyte migration, and epithelial-mesenchymal transition. Our past work has shown HB-EGF is a primary marker of profibrotic M2 macrophages, and this study seeks to characterize myeloid-derived HB-EGF and its primary mechanism of action in bleomycin-induced lung fibrosis using Hbegff/f;Lyz2Cre+ mice. Here, we show that patients with IPF and mice with pulmonary fibrosis have increased expression of HB-EGF and that lung macrophages and transitional AECs of mice with pulmonary fibrosis and humans all express HB-EGF. We also show that Hbegff/f;Lyz2Cre+ mice are protected from bleomycin-induced fibrosis and that this protection is likely multifactorial, caused by decreased CCL2-dependent monocyte migration, decreased fibroblast migration, and decreased contribution of HB-EGF from AEC sources when HB-EGF is removed under the Lyz2Cre promoter.
Correspondence and requests for reprints should be addressed to Bethany B. Moore, Ph.D., Department of Internal Medicine, University of Michigan, 4053 BSRB,109 Zina Pitcher Place, Ann Arbor, MI 48109-2200. E-mail: [email protected].*Co–senior authors.
Supported by the National Heart, Lung, and Blood Institute grants F31 HL149150 (E.M.H.), R35 HL144481 (B.B.M.), and R01 HL147920 (R.L.Z); the Center for Strategic Scientific Initiatives, National Cancer Institute grants R01 CA247516 and U01 CA224145 (H.C.C.); the Division of Intramural Research, National Institute of Allergy and Infectious Diseases grant T32 AI007413 (E.M.H.); Francis Family Foundation (S.J.G.); Michigan Institute for Clinical and Health Research (S.J.G.); and Boehringer Ingelheim (S.J.G.).
Author Contributions: E.M.H., H.C.C., and B.B.M. conceived and designed research. E.M.H. and A.R. performed experiments. E.M.H. and S.J.G. analyzed data. E.M.H. and B.B.M. interpreted results of experiments. E.M.H., S.J.G., Y.W., D.N.O’D., and R.L.Z. prepared figures. S.M. conducted SOMAmer statistics. E.M.H. drafted manuscript. E.M.H. and B.B.M. edited and revised manuscript. E.M.H., S.J.G., D.N.O’D., S.M., R.L.Z., H.C.C., and B.B.M. approved the final version of manuscript.
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Originally Published in Press as DOI: 10.1165/rcmb.2022-0174OC on August 29, 2022
Author disclosures are available with the text of this article at www.atsjournals.org.
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