The synergistic interaction of gastric acid and food material in the pathogenesis of aspiration pneumonitis
Davidson, Bruce Alan
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Gastric aspiration pneumonitis occurs when gastric contents enter the lungs, due to compromised protective airway reflexes, and initiate an acute inflammatory response. Although a majority of such events produce a mild, rapidly resolving pneumonitis with little or no serious sequelae, approximately 15% of these cases develop Acute Lung Injury/Acute Respiratory Distress Syndrome (ALI/ARDS) that carry a greater than 30% mortality. Little is known as to what directs the gastric aspiration event to progress through a mild pneumonitis as opposed to the development of ALI/ARDS. The global hypothesis tested in this study was that the ALI/ARDS course is manifest when the aspirate is composed of two or more gastric components, namely, acid and food particles, in sufficient quantities such that the inflammatory responses associated with either of them alone combine to produce a synergistic increase in lung injury. Our laboratory has established rat and mouse models of the synergistic lung injury associated with the aspiration of gastric acid and food particles. These models were utilized to further dissect the inflammatory responses from instillation of normal saline (NS) + HCl, pH = 1.25 (Acid), NS + food particles (SNAP), or NS + food particles + HCl, pH = 1.25 (CASP). At appropriate times post-injury, bronchoalveolar lavage (BAL) was performed and the recovered fluid (BALF) analyzed for airway infiltration of neutrophils (PMN), BALF albumin concentration (as a measure of lung injury), and numerous inflammatory cytokines and chemokines concentrations determined by ELISA or bioassay. Manipulations of the model, such as inducing neutropenia prior to the injury, altering the sequence of the different aspirate instillations, utilizing NADPH oxidase (PhOx) and Nrf2 knockout mice, and treatment with CDDO-Im (a direct activator of Nrf2) following injury constituted the main experimental methodology utilized in this study. Synergistic interaction was determined in these models by 2-way ANOVA. In addition, to investigate the effect of direct acid-induced injury to the alveolar macrophage (aMØ) on elaboration of pro-inflammatory cytokine/chemokine signals, an in vitro aMØ low pH exposure model was employed and released cytokines/chemokines assessed by ELISA or bioassay, as well as nuclear translocation of the pro-inflammatory transcription factors, NF-κB and phos-c-Jun by immunofluorescence microscopy. The seminal findings in these rat and mouse studies are: 1) the synergism peaks at 4-8 hr post-injury, but can still be observed up to 48 hr post-injury; 2) synergism still occurs when an initial acid insult is separated from the food particle insult by up to 4 hr (possibly up to < 10 hr) and then becomes antagonistic with 14 – 24 hr of separation of the insults; 3) an initial (or concurrent) acid injury is required for the synergism and when food particles are instilled into the lung 4 hr prior to instillation of the acid vehicle the resulting lung injury is antagonistic; 4) lung injury correlates with PMN “injury potential”; 5) pulmonary TNFα levels correlate with PMN “injury potential”; 6) PMNs are required for the synergistic increase in the severity of the lung injury; 7) exposure of aMØ to transient low pH may contribute to reduced TNFα levels through inhibition of NF-κB transcription signaling; 8) PhOx activity is required for synergistic interaction, but Nrf2 activation is not; 9) accentuation of Nrf2 activation by CDDO-Im reduces lung injury suggests a potential therapeutic strategy for gastric aspiration pneumonitis. The results of this study indicate potential targets for the development of effective therapeutic interventions for gastric aspiration pneumonitis in an attempt to avert the potential ALI/ARDS course. The wide ranging etiologies of ALI/ARDS, encompassing direct and indirect, and infectious and non-infectious stimuli make the search for effective therapies all that much harder. The studies described here may shed some light to direct future studies to focus on the interaction of multiple inflammatory stimuli that may elaborate the deadly ALI/ARDS expression of those pathologies.