Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Modest supplemental oxygen worsens lung injury in a murine model of sepsis


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Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are associated with high levels of morbidity and mortality, imposing a substantial burden on the health care system. Sepsis is a frequent cause of ALI making the study of sepsis-induced lung injury crucial. Using systemic lipopolysaccharide (LPS) we observed predominantly interstitial lung injury with a paucity of alveolar neutrophils and damage, dramatically different from the prominent alveolar injury and neutrophil influx seen with direct lung injury. Along the way to understanding the difference between direct and indirect injury in mice, we postulated that 50% oxygen would augment lung injury in mice after systemic insult compared to LPS or 50% oxygen alone. Our injury model consists of LPS followed 12 hrs later by exposure to 50% or 21% oxygen for 60 hrs. At day 3, mice exposed to LPS plus oxygen showed a synergistically increase lung injury, with a prominent alveolar component, compare to other groups. We hypothesize that the addition of 50% oxygen to LPS increases oxidative stress and inflammatory cytokine production, thereby augmenting lung injury, and that injury can be mitigated with antioxidant therapy. We plan to examine aspects of this hypothesis with following 2 aims: 1. To examine potential mechanisms driving the augmentation of lung injury by combined exposure to LPS and supplemental oxygen. Mice exposed to LPS, 50% oxygen, or LPS plus oxygen, will be assessed for mortality, weight loss; BAL cell counts, differentials, total protein, wet lung weight; and histology. In addition, we will measure: intracellular and extracellular ROS generation; lung anti-oxidant enzyme levels; BAL/Lung cytokines; and alveolar cell apoptosis at defined intervals. In vitro, we will incubate naive alveolar macrophages (AMs) and dendritic cells (DCs) with LPS, 50% oxygen, or in combination, and measure ROS production and key inflammatory mediators previously identified. 2. To determine if NAc therapy concurrent with supplemental oxygen abrogates lung injury, and examine potential mechanisms of that effect. NAc or control will be given to groups as in Aim 1, and the effect on injury patterns will be assessed. In addition, we will examine cytokine and anti-oxidant potential pathways indicated by Aim 1 findings, as well as time- and cell-specific ROS and apoptosis activity. Public Health Relevance: Significant injury to the lungs requiring hospitalization and death can occur from systemic illness. We will examine the role of moderate oxygen as a potential amplifier of that injury in an animal model. This work has the potential to improve human outcomes and decrease burden on the health care system from this devastating illness.


Collapse sponsor award id
F32HL090200

Collapse Time 
Collapse start date
2008-08-01
Collapse end date
2009-06-30

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