Myeloid cell dynamics in bleomycin-induced pulmonary injury in mice; effects of anti-TNFα antibody
Bleomycin is a cancer therapeutic known to cause lung injury which progresses to fibrosis. Evidence suggests that macrophages contribute to this pathological response. Tumor necrosis factor (TNF)α is a macrophage-derived pro-inflammatory cytokine implicated in lung injury. Herein, we investigated th...
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Published in | Toxicology and applied pharmacology Vol. 417; p. 115470 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Inc
15.04.2021
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Subjects | |
Online Access | Get full text |
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Summary: | Bleomycin is a cancer therapeutic known to cause lung injury which progresses to fibrosis. Evidence suggests that macrophages contribute to this pathological response. Tumor necrosis factor (TNF)α is a macrophage-derived pro-inflammatory cytokine implicated in lung injury. Herein, we investigated the role of TNFα in macrophage responses to bleomycin. Treatment of mice with bleomycin (3 U/kg, i.t.) caused histopathological changes in the lung within 3 d which culminated in fibrosis at 21 d. This was accompanied by an early (3–7 d) influx of CD11b+ and iNOS+ macrophages into the lung, and Arg-1+ macrophages at 21 d. At this time, epithelial cell dysfunction, defined by increases in total phospholipids and SP-B was evident. Treatment of mice with anti-TNFα antibody (7.5 mg/kg, i.v.) beginning 15–30 min after bleomycin, and every 5 d thereafter reduced the number and size of fibrotic foci and restored epithelial cell function. Flow cytometric analysis of F4/80+ alveolar macrophages (AM) isolated by bronchoalveolar lavage and interstitial macrophages (IM) by tissue digestion identified resident (CD11b−CD11c+) and immature infiltrating (CD11b+CD11c−) AM, and mature (CD11b+CD11c+) and immature (CD11b+CD11c−) IM subsets in bleomycin treated mice. Greater numbers of mature (CD11c+) infiltrating (CD11b+) AM expressing the anti-inflammatory marker, mannose receptor (CD206) were observed at 21 d when compared to 7 d post bleomycin. Mature proinflammatory (Ly6C+) IM were greater at 7 d relative to 21 d. These cells transitioned into mature anti-inflammatory/pro-fibrotic (CD206+) IM between 7 and 21 d. Anti-TNFα antibody heightened the number of CD11b+ AM in the lung without altering their activation state. Conversely, it reduced the abundance of mature proinflammatory (Ly6C+) IM in the tissue at 7 d and immature pro-fibrotic IM at 21 d. Taken together, these data suggest that TNFα inhibition has beneficial effects in bleomycin induced injury, restoring epithelial function and reducing numbers of profibrotic IM and the extent of pulmonary fibrosis.
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•Intratracheal bleomycin increases macrophage recruitment to the lung up to 21 days.•Bleomycin induced a time dependent shift of pro to anti inflammatory interstitial macrophages.•Fibrosis and macrophage phenotype switch were accompanied by epithelial dysfunction.•TNFα antibody treatment reduced macrophage activation, fibrosis, and epithelial dysfunction. |
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Bibliography: | Debra Laskin Supervision; Writing - review & editing. Alexa Murray Data curation, Formal analysis; Methodology. Andrew Gow Conceptualization; Project administration; Funding acquisition; Writing - original draft; Writing - review & editing. The authors contributed equally to this manuscript. Credit author statement Sheryse Taylor Data curation, Formal analysis; Methodology. Rama Malaviya Conceptualization; Data curation. Thea Golden Data curation, Formal analysis; Methodology; Visualization; Writing - original draft; Writing - review & editing. Elena Abramova Formal analysis; Methodology. Alessandro Venosa Conceptualization; Data curation, Formal analysis; Visualization; Writing - original draft; Writing - review & editing. James Gow Data curation, Formal analysis; Validation; Methodology; Writing - original draft. |
ISSN: | 0041-008X 1096-0333 |
DOI: | 10.1016/j.taap.2021.115470 |