Journal
THORAX
Volume 73, Issue 4, Pages 321-330Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/thoraxjnl-2017-210105
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Funding
- Instituto de Salud Carlos II (Plan estatal I+ D+ i) [PI16/1614]
- Fundacion para el fomento en Asturias de la investigacion cientifica aplicada y la tecnologia (FICYT) [GRUPIN14-089]
- Instituto de Salud Carlos II (Contratos Sara Borrell) [CD16/00033]
- Instituto de Salud Carlos II (Contratos Rio Hortega) [CM16/00128]
- Instituto de Salud Carlos II [INT-15/002]
- Fundacion Bancaria Caja de Ahorros de Asturias
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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 alpha, interferon gamma 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.
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