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Original Article
Impaired lung repair during neutropenia can be reverted by matrix metalloproteinase-9
  1. Jorge Blázquez-Prieto1,2,3,
  2. Inés López-Alonso1,2,3,
  3. Laura Amado-Rodríguez2,3,
  4. Covadonga Huidobro2,3,
  5. Adrián González-López3,4,
  6. Wolfgang M Kuebler5,
  7. Guillermo M Albaiceta1,2,3
  1. 1 Departamento de Biología Funcional, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain
  2. 2 Unidad de Cuidados Intensivos Cardiológicos, Área del Corazón, Hospital Universitario Central de Asturias, Oviedo, Spain
  3. 3 Instituto de Investigación Biosanitaria del Principado de Asturias, Oviedo, Spain
  4. 4 Department of Anesthesiology and Operative Intensive Care Medicine, Charité Universitätsmedizin, Berlin, Germany
  5. 5 Institute of Physiology, Charité Universitätsmedizin, Berlin, Germany
  1. Correspondence to Dr Guillermo M Albaiceta, Unidad de Cuidados Intensivos Cardiológicos, Área del Corazón, Hospital Universitario Central de Asturias, Avda de Roma s/n, Oviedo 33011, Spain; guillermo.muniz{at}


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.

  • ARDS
  • immunodeficiency
  • lung proteases
  • Neutrophil Biology

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  • JB-P and IL-A contributed equally.

  • Contributors JB-P, IL-A and GMA designed the study and analysed the data. JB-P, IL-A, LA-R, CH and AG-L performed the experiments. JB-P, IL-A, WMK and GMA discussed the results and wrote the manuscript.

  • Funding Supported by Instituto de Salud Carlos III (Plan estatal I+D+i, PI16/1614, FEDER funds). IL-A is the recipient of a grant from Fundación para el fomento en Asturias de la investigación científica aplicada y la tecnología (FICYT, GRUPIN14-089, Consejería de Hacienda, Principado de Asturias, Spain). CH is the recipient of a grant from Instituto de Salud Carlos III (Contratos Sara Borrell, CD16/00033). LA-R is the recipient of a grant from Instituto de Salud Carlos III (Contratos Rio Hortega, CM16/00128). GMA is the recipient of a grant from Instituto de Salud Carlos III (INT-15/002). Instituto Universitario de Oncología is supported by Fundación Bancaria Caja de Ahorros de Asturias.

  • Competing interests None declared.

  • Ethics approval The Animal Research Ethics Committee of the Universidad de Oviedo evaluated and approved the study. The patient part of the protocol was reviewed and approved by the regional ethics committee (Comité Ético de Investigación Clínica del Principadode Asturias, Spain).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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