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Comparative Study
. 2011 Sep 1;184(5):569-81.
doi: 10.1164/rccm.201010-1719OC.

Ly6Chi monocytes direct alternatively activated profibrotic macrophage regulation of lung fibrosis

Michael A Gibbons  1 , Alison C MacKinnon, Prakash Ramachandran, Kevin Dhaliwal, Rodger Duffin, Alexander T Phythian-Adams, Nico van Rooijen, Christopher Haslett, Sarah E Howie, A John Simpson, Nikhil Hirani, Jack Gauldie, John P Iredale, Tariq Sethi, Stuart J Forbes
Affiliations
Comparative Study

Ly6Chi monocytes direct alternatively activated profibrotic macrophage regulation of lung fibrosis

Michael A Gibbons et al. Am J Respir Crit Care Med. .

Abstract

Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating disease. Antiinflammatory therapies, including corticosteroids, are of no benefit. The role of monocytes and macrophages is therefore controversial.

Objectives: To define the role of monocytes and macrophages during lung fibrogenesis and resolution, and explore the phenotype of the cells involved.

Methods: We used multiple in vivo depletional strategies, backed up by adoptive transfer techniques. Further studies were performed on samples from patients with IPF.

Measurements and main results: Depletion of lung macrophages during fibrogenesis reduced pulmonary fibrosis as measured by lung collagen (P = 0.0079); fibrosis score (P = 0.0051); and quantitative polymerase chain reaction for surrogate markers of fibrosis Col1 (P = 0.0083) and a-smooth muscle actin (P = 0.0349). There was an associated reduction in markers of the profibrotic alternative macrophage activation phenotype, Ym1 (P = 0.0179), and Arginase 1. The alternative macrophage marker CD163 was expressed on lung macrophages from patients with IPF. Depletion of Ly6Chi circulating monocytes reduced pulmonary fibrosis (P = 0.0052) and the number of Ym1- positive alternatively activated lung macrophages (P = 0.0310). Their adoptive transfer during fibrogenesis exacerbated fibrosis (P = 0.0304); however, adoptively transferred CD45.1 Ly6Chi cells were not found in the lungs of recipient CD45.2 mice.

Conclusions: We demonstrate the importance of circulating monocytes and lung macrophages during pulmonary fibrosis, and emphasize the importance of the alternatively activated macrophage phenotype. We show that Ly6Chi monocytes facilitate the progression of pulmonary fibrosis, but are not obviously engrafted into lungs thereafter. Finally, we provide empirical data to suggest that macrophages may have a resolution-promoting role during the reversible phase of bleomycin-induced pulmonary fibrosis.

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Comment in

  • The lung macrophage: a Jack of all trades.
    Misharin AV, Scott Budinger GR, Perlman H. Misharin AV, et al. Am J Respir Crit Care Med. 2011 Sep 1;184(5):497-8. doi: 10.1164/rccm.201107-1343ED. Am J Respir Crit Care Med. 2011. PMID: 21885631 Free PMC article. No abstract available.

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