Synergy between acid and endotoxin in an experimental model of aspiration-related lung injury progression

Abstract

Aspiration is a common cause of lung injury, but it is unclear why some cases are self-limited while others progress to acute respiratory distress syndrome (ARDS). Sporadic exposure to more than one insult could account for this variable progression. We investigated whether synergy between airway acid and endotoxin (LPS) amplifies injury severity in mice and whether LPS levels in human patients could corroborate our experimental findings. C57BL/6 mice aspirated acid (pH 1.3) or normal saline (NS), followed by LPS aerosol or nothing. Bronchoalveolar lavage fluid (BALF) was obtained 2 to 49 h later. Mice were injected with FITC-dextran 25 h after aspiration and connected to a ventilator, and lung elastance (H) measured periodically following deep inflation (DI). Endotracheal and gastric aspirates were also collected from patients in the intensive care unit and assayed for pH and LPS. Lung instability (ΔH following DI) and pressure-volume hysteresis in acid- or LPS-exposed mice was greater than in controls but markedly greater in the combined acid/LPS group. BALF neutrophils, cytokines, protein, and FITC-dextran in the acid/LPS mice were geometrically higher than all other groups. BALF from acid-only mice markedly amplified LPS-induced TNF-α production in cultured macrophages. Human subjects had variable endotracheal LPS levels with the highest burden in those at higher risk of aspiration. Acid aspiration amplifies LPS signaling in mice to disrupt barrier function and lung mechanics in synergy. High variation in airway LPS and greater airway LPS burden in patients at higher risk of aspiration could help explain the sporadic progression of aspiration to ARDS.

Capturing the multifactorial nature of ARDS - “Two-hit” approach to model murine acute lung injury

“…3C and F). Of note, cellularity and MPO in BALF of the acid exposed animals (both in animals solely exposed to HCl and in combination with VILI) display a greater variability than the mice exposed to LPS, which is comparable with prior studies (Kennedy et al 1989;Tetenev et al 2015). Which is in line with clinical observations, that some patients will develop a mild self-limiting pneumonitis after aspiration, whereas others progress to severe ARDS (Warner et al 1993).…”

“…; Tetenev et al. ). Which is in line with clinical observations, that some patients will develop a mild self‐limiting pneumonitis after aspiration, whereas others progress to severe ARDS (Warner et al.…”

“…; Tetenev et al. ), our goal with this study was comparing i.t LPS, respectively, HCL (simulating acid aspiration) followed by VILI. We hypothesized that exposing the lungs to an initial injury prior to inducing a secondary lung injury with VILI would lead to a superadditive effect in ALI compared to the animals only exposed to VILI.…”

“…Murine models remain essential to study underlying mechanisms of ALI/ARDS as human patients have multiple clinical variables, which cannot be controlled. Various combined ALI models have been described previously (Yamada et al 2000;Pfeifer et al 2015;Tetenev et al 2015), our goal with this study was comparing i.t LPS, respectively, HCL (simulating acid aspiration) followed by VILI. We hypothesized that exposing the lungs to an initial injury prior to inducing a secondary lung injury with VILI would lead to a superadditive effect in ALI compared to the animals only exposed to VILI.…”

The anesthetic agent sevoflurane attenuates pulmonary acute lung injury by modulating apoptotic pathways

“…Pneumonia and aspiration of gastric contents account for most cases of direct lung injury while sepsis is the major cause of indirect lung injury ( 17 , 18 ). The most commonly used experimental models of direct lung injury are those using intratracheal LPS administration, mechanical ventilation or acid aspiration ( 19 ). Unfortunately, these simulate events that are often encountered in clinical anesthesia, so we chose a direct lung injury model for our study.…”