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J Autoimmun. 2019 Jun;100:120-130. doi: 10.1016/j.jaut.2019.03.009. Epub 2019 Mar 28.

Neutrophil extracellular traps are associated with the pathogenesis of diffuse alveolar hemorrhage in murine lupus.

Author information

1
Aix-Marseille Univ, INSERM, INRA, C2VN, Marseille, France; Department of Internal Medicine and Clinical Immunology CHU Conception, Assistance Publique-Hôpitaux de Marseille (AP-HM), Marseille, France. Electronic address: pierre.jarrot@ap-hm.fr.
2
Aix-Marseille Univ, INSERM, INRA, C2VN, Marseille, France.
3
Laboratory of Pathology, CHU La Timone, AP-HM, Marseille, France.
4
Laboratory of Pathology, CHU Nord, AP-HM, Marseille, France.
5
Aix-Marseille Univ, INSERM, INRA, C2VN, Marseille, France; Laboratory of Haematology, CHU La Conception, AP-HM, Marseille, France.
6
Aix-Marseille Univ, INSERM, INRA, C2VN, Marseille, France; Department of Internal Medicine and Clinical Immunology CHU Conception, Assistance Publique-Hôpitaux de Marseille (AP-HM), Marseille, France.

Abstract

Diffuse alveolar hemorrhage (DAH) is a life-threatening complication of systemic lupus erythematosus (SLE) and systemic vasculitis. Although initially described to have antibacterial properties, increasing evidence suggests that neutrophil extracellular traps (NETs) have a detrimental role in both autoimmune diseases and acute lung injury. We investigated whether NETs could be detected in a murine model of pristane-induced lupus DAH and contribute to lung injury. Such NETs might constitute a therapeutic target. NETs were characterized by immunofluorescence staining of DNA, neutrophil elastase and citrullinated histones. Evaluation of lung injury was performed by haematoxylin-eosin staining and a quantification program. Clinical status of the mice was assessed by measurement of arterial oxygen saturation and survival curves after recombinant human deoxyribonuclease-1 (Rh-DNase-1) inhalations or polymorphonuclear neutrophil (PMN) depletion. Pristane was found to promote NETs formation in vitro and in vivo. Treatment of mice with Rh-DNase-1 inhalations cleared NETs and reduced lung injury. Clinical status improved significantly, with increased arterial oxygenation and survival. Following PMN depletion, NETs were absent with a subsequent reduction of lung injury and improved arterial oxygenation. These results support a pathogenic role of PMNs and NETs in lung injury during pristane-induced DAH. Targeting NETs with Rh-DNase-1 inhalations could constitute an interesting adjuvant therapy in human DAH.

KEYWORDS:

Deoxyribonuclease-1; Diffuse alveolar hemorrhage; Murine model; Neutrophil extracellular traps; Systemic lupus erythematosus

PMID:
30930069
DOI:
10.1016/j.jaut.2019.03.009

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