Abstract
Acute lung injury (ALI), a common cause of morbidity and mortality in intensive care units, results from either direct intra-alveolar injury or indirect injury following systemic inflammation and oxidative stress. Adequate tissue oxygenation often requires additional supplemental oxygen. However, hyperoxia causes lung injury and pathological changes. Notably, preclinical data suggest that aspirin modulates numerous platelet-mediated processes involved in ALI development and resolution. Our previous study suggested that prehospital aspirin use reduced the risk of ALI in critically ill patients. This research uses an in vivo imaging system (IVIS) to investigate the mechanisms of aspirin’s anti-inflammatory and antioxidant effects on hyperoxia-induced ALI in nuclear factor κB (NF-κB)–luciferase transgenic mice. To define mechanisms through which NF-κB causes disease, we developed transgenic mice that express luciferase under the control of NF-κB, enabling real-time in vivo imaging of NF-κB activity in intact animals. An NF-κB-dependent bioluminescent signal was used in transgenic mice carrying the luciferase genes to monitor the anti-inflammatory effects of aspirin. These results demonstrated that pretreatment with aspirin reduced luciferase expression, indicating that aspirin reduces NF-κB activation. In addition, aspirin reduced reactive oxygen species expression, the number of macrophages, neutrophil infiltration and lung edema compared with treatment with only hyperoxia treatment. In addition, we demonstrated that pretreatment with aspirin significantly reduced the protein levels of phosphorylated protein kinase B, NF-κB and tumor necrosis factor α in NF-κB–luciferase+/+ transgenic mice. Thus, the effects of aspirin on the anti-inflammatory response and reactive oxygen species suppressive are hypothesized to occur through the NF-κB signaling pathway. This study demonstrated that aspirin exerts a protective effect for hyperoxia-induced lung injury and thus is currently the drug conventionally used for hyperoxia-induced lung injury.
Highlights
Acute respiratory distress syndrome (ARDS), or acute lung injury (ALI), is a common and devastating syndrome contributing to serious morbidities and mortality in critically ill patients
Prolonged hyperoxic exposure can exacerbate the pathogenic processes within the lung [5], cause the generation of reactive oxygen species (ROS) [6] and increase apoptotic signaling [7], all of which may result in hyperoxia-induced ALI [8,9], causing pathological changes resembling ARDS in animal models [10]
Part II: The homozygous transgenic mice (NF-κB–luciferase+/+ ) were randomly assigned to four groups for pretreatment (n = 6): (1) negative control, (2) pretreatment with PBS for 3 days followed by exposure to 72 h of hyperoxia, (3) pretreatment with a low dose of aspirin (12.5 μg/g) for 3 days followed by exposure to 72 h of hyperoxia and (4) pretreatment with a high dose of aspirin (100 μg/g) for 3 days followed by exposure to 72 h of hyperoxia
Summary
Acute respiratory distress syndrome (ARDS), or acute lung injury (ALI), is a common and devastating syndrome contributing to serious morbidities and mortality in critically ill patients. The pathophysiologic features of ARDS include dysregulated inflammation, inappropriate accumulation and activity of leukocytes and platelets, uncontrolled activation of coagulation pathways, and altered permeability of the alveolar endothelial and epithelial barriers [1,2,3], leading to the impairment of oxygenation and subsequent respiratory failure. Numerous promising therapies have effectively prevented ARDS in experimental models, successful translation to clinical applications is still lacking [11,12,13]. The possible mechanisms by which platelets contribute to ARDS include the activation of endothelial cells by release of proinflammatory mediators [14,15,16] and the adherence of platelets to lung capillary endothelial cells, thereby activating attached leukocytes [17]. Experimental studies have shown that in models of transfusion-related ALI, lipopolysaccharide-induced ALI and hydrochloric acid-induced ALI, aspirin can prevent or treat
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