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Thorax. 2018 Apr;73(4):321-330. doi: 10.1136/thoraxjnl-2017-210105. Epub 2017 Sep 25.

Impaired lung repair during neutropenia can be reverted by matrix metalloproteinase-9.

Author information

1
Departamento de Biología Funcional, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain.
2
Unidad de Cuidados Intensivos Cardiológicos, Área del Corazón, Hospital Universitario Central de Asturias, Oviedo, Spain.
3
Instituto de Investigación Biosanitaria del Principado de Asturias, Oviedo, Spain.
4
Department of Anesthesiology and Operative Intensive Care Medicine, Charité Universitätsmedizin, Berlin, Germany.
5
Institute of Physiology, Charité Universitätsmedizin, Berlin, Germany.
#
Contributed equally

Abstract

BACKGROUND:

Neutrophils may cause tissue disruption during migration and by releasing cytotoxic molecules. However, the benefits of neutrophil depletion observed in experimental models of lung injury do not correspond with the poor outcome of neutropenic patients.

METHODS:

To clarify the role of neutrophils during repair, mice with ventilator induced lung injury (VILI) were rendered neutropenic after damage, and followed for 48 hours of spontaneous breathing. Lungs were harvested and inflammatory mediators and matrix metalloproteinases measured. Bronchoalveolar lavage fluid (BALF) from ventilated patients with acute respiratory distress syndrome, with or without neutropenia, was collected, the same mediators measured and their effects in an ex vivo model of alveolar repair studied. Finally, neutropenic mice were treated after VILI with exogenous matrix metalloproteinase-9 (MMP-9).

RESULTS:

Lungs from neutropenic animals showed delayed repair and displayed higher levels of tumour necrosis factor α, interferon γ and macrophage inflammatory protein 2, and absence of MMP-9. BALF from ventilated neutropenic patients with acute respiratory distress syndrome showed similar results. BALFs from neutropenic patients yielded a delayed closure rate of epithelial wounds ex vivo, which was improved by removal of collagen or addition of exogenous MMP-9. Lastly, treatment of neutropenic mice with exogenous MMP-9 after VILI reduced tissue damage without modifying cytokine concentrations.

CONCLUSION:

Release of MMP-9 from neutrophils is required for adequate matrix processing and lung repair.

KEYWORDS:

ARDS; Neutrophil Biology; immunodeficiency; lung proteases

PMID:
28947666
DOI:
10.1136/thoraxjnl-2017-210105
[Indexed for MEDLINE]

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