Role of dual oxidases in ventilator-induced lung injury

Laura Cagle, Angela Linderholm, Lisa Franzi, Sabrina Hoehne, Jerold Last, Nicholas Kenyon, Beate Illek, Richart Harper

Research output: Contribution to journalArticlepeer-review

Abstract

Positive-pressure ventilation results in ventilator-induced lung injury, and few therapeutic modalities have been successful at limiting the degree of injury to the lungs. Understanding the primary drivers of ventilator-induced lung injury will aid in the development of specific treatments to ameliorate the progression of this syndrome. There are conflicting data for the role of neutrophils in acute respiratory distress syndrome pathogenesis. Here, we specifically examined the importance of neutrophils as a primary driver of ventilator-induced lung injury in a mouse model known to have impaired ability to recruit neutrophils in previous models of inflammation. We exposed Duoxa1/1 and Duoxa2/2 mice to low-or high-tidal volume ventilation with or without positive end-expiratory pressure (PEEP) and recruitment maneuvers for 4 hours. Absolute neutrophils in BAL fluid were significantly reduced in Duoxa2/2 mice compared with Duoxa1/1 mice (6.7 cells/ml; 16.4 cells/ml; P = 0.003), consistent with our hypothesis that neutrophil translocation across the capillary endothelium is reduced in the absence of DUOX1 or DUOX2 in response to ventilator-induced lung injury. Reduced lung neutrophilia was not associated with a reduction in overall lung injury in this study, suggesting that neutrophils do not play an important role in early features of acute lung injury. Surprisingly, Duoxa2/2 mice exhibited significant hypoxemia, as measured by the arterial oxygen tension/fraction of inspired oxygen ratio and arterial oxygen content, which was out of proportion with that seen in the Duoxa1/1 mice (141, 257, P = 0.012). These findings suggest a role for dual oxidases to limit physiologic impairment during early ventilator-induced lung injury.

Original languageEnglish (US)
Pages (from-to)208-215
Number of pages8
JournalAmerican journal of respiratory cell and molecular biology
Volume64
Issue number2
DOIs
StatePublished - 2021

Keywords

  • Acute lung injury
  • Dual oxidases
  • NADPH oxidases
  • Positive-pressure ventilation

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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