• Am. J. Respir. Crit. Care Med. · Oct 2019

    Role of B7H3/IL-33 Signaling in Pulmonary Fibrosis-induced Profibrogenic Alterations in Bone Marrow.

    • Taku Nakashima, Tianju Liu, Biao Hu, Zhe Wu, Matthew Ullenbruch, Keitaro Omori, Lin Ding, Noboru Hattori, and Sem H Phan.
    • Department of Molecular and Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; and.
    • Am. J. Respir. Crit. Care Med. 2019 Oct 15; 200 (8): 103210441032-1044.

    AbstractRationale: The impact of lung insult on the bone marrow (BM) and subsequent disease is unknown.Objectives: To study alterations in the BM in response to lung injury/fibrosis and examine their impact on subsequent lung insult.Methods: BM cells from control or bleomycin-treated donor mice were transplanted into naive mice, which were subsequently evaluated for bleomycin-induced pulmonary fibrosis. In addition, the effect of prior bleomycin treatment on subsequent fibrosis was examined in wild-type and B7H3-knockout mice. Samples from patients with idiopathic pulmonary fibrosis were analyzed for potential clinical relevance of the findings.Measurements and Main Results: Recipient mice transplanted with BM from bleomycin-pretreated donors showed significant exacerbation of subsequent fibrosis with increased B7H3+ cell numbers and a T-helper cell type 2-skewed phenotype. Pretreatment with a minimally fibrogenic/nonfibrogenic dose of bleomycin also caused exacerbation, but not in B7H3-deficient mice. Exacerbation was not observed if the mice received naive BM cell transplant after the initial bleomycin pretreatment. Soluble B7H3 stimulated BM Ly6Chi monocytic cell expansion in vitro and caused similar expansion in the lung in vivo. Notably, soluble B7H3 was elevated in plasma of patients with idiopathic pulmonary fibrosis and in BAL fluid in those with acute exacerbation. Finally, ST2 deficiency diminished the bleomycin-induced B7H3 and IL-13 upregulation, suggesting a role for type 2 innate lymphoid cells.Conclusions: Pulmonary fibrosis caused significant alterations in BM with expansion and activation of monocytic cells, which enhanced fibrosis when transplanted to naive recipients with potential mediation by a novel role for B7H3 in the pathophysiology of pulmonary fibrosis in both mice and humans.

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