Cerebral Concussion Primes the Lungs for Subsequent Neutrophil-Mediated Injury

Objectives: Mild traumatic brain injury in the form of concussion is extremely common, and the potential effects on pulmonary priming have been underestimated. The aim of this study was to characterize the pulmonary response following mild traumatic brain injury and assess the pulmonary susceptibility to lung injury after a subsequent innocuous pulmonary insult. Design: Experimental in vivo study. Setting: University research laboratory. Subjects: Male CD1 mice. Interventions: We developed a model of concussive traumatic brain injury in mice followed by pulmonary acid microaspiration. To assess the dependent role of neutrophils in mediating pulmonary injury, we specifically depleted neutrophils. Measurements and Main Results: Lateral fluid percussion to the brain resulted in neuronal damage and neutrophil infiltration as well as extensive pulmonary interstitial neutrophil accumulation but no alveolar injury. Following subsequent innocuous acid microaspiration, augmented alveolar neutrophil influx led to the development of pulmonary hemorrhage that was reduced following neutrophil depletion. Conclusions: This model shows for the first time that innocuous acid microaspiration is sufficient to induce neutrophil-mediated lung injury following mild concussion and that the extracranial effects of mild traumatic brain injury have been underestimated. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Drs. Andrews, Rhodes, and Dhaliwal conceived the project. Drs. Humphries, Rhodes, and Dhaliwal designed the experiments. Dr. Humphries, Dr. O'Neill, and Ms. Scholefield performed experiments. Drs. Dorward and Rhodes provided methods. Drs. Mackinnon, Rossi, Haslett, Andrews, and Rhodes provided guidance and edited the article. Drs. Humphries and Dhaliwal wrote the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/29S62lw). Supported mainly by a U.K. Medical Research Council (MRC) PhD Studentship to Dr. Humphries. Also supported by the MRC (MR/K013386/1 [Drs. Rossi and Haslett]) and the Wellcome Trust WT096497 (Dr. Dorward). Dr. Dorward received support for article research from Wellcome Trust/Charity Open Access Fund. Drs. Humphries and Haslett received support for article research from Research Councils UK (RCUK). Dr. Dorward's institution received funding from Wellcome Trust. Dr. Haslett's institution received funding from Medical Research Council studentship. Drs. Haslett and Dhaliwal received funding from Edinburgh Molecular Imaging. The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Duncan C. Humphries or Kevin Dhaliwal, MRC Centre for Inflammation Research, University of Edinburgh, 47 Little France Crescent, Edinburgh, United Kingdom. E-mail: Duncan.Humphries@ed.ac.uk; Kev.Dhaliwal@ed.ac.uk Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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