Abstract
This study aimed to ascertain whether endoplasmic reticulum (ER) stress participates in acute lung injury (ALI) and related right ventricular dysfunction (RVD) as well as to explore the underlying mechanisms of these conditions. A single intratracheal instillation of lipopolysaccharide (LPS) (10 mg/kg) was used to establish the RVD model. The ER stress inhibitor, 4-PBA (500 mg/kg), was administered using a gavage 2 hours before and after the LPS treatment for prevention and treatment, respectively. At 12 hours post-LPS exposure, mRNA and protein expressions of ER stress-specific biomarkers, glucose regulating protein 78 (GRP78) and CCAAT/enhancer binding protein homology (CHOP), were significantly upregulated. This effect was inhibited by both 4-PBA prevention and treatment. In addition, echocardiography showed that 4-PBA improved the LPS-induced abnormality in the tricuspid annular plane systolic excursion (TAPSE) and the right ventricular end-diastolic diameter (RVEDD), however not in the pulmonary artery acceleration time (PAAT). Furthermore, hematoxylin and eosin staining (HE) and terminal transferase dUTP nick end labeling (TUNEL) assays revealed that the proportion of proapoptotic cells was higher in RVD rats. This was prominently ameliorated by 4-PBA treatment. Moreover, 4-PBA had a similar reverse effect on the LPS-induced increase in the Bax/Bcl-2 ratio, caspase-12, and caspase-3 expressions as revealed by western blotting. Furthermore, 4-PBA improved LPS-induced right ventricle (RV) myeloperoxidase (MPO)-positive neutrophil infiltration percentage, inhibited nuclear factor kappa B (NF-κB) activity, and reduced the expressions of inflammatory cytokines, TNF-α, IL-1β, and IL-6, in serum and RV. Taken together, our results indicated that ER stress-mediated apoptosis and inflammation might contribute to the development of ALI-related RVD induced by intratracheal LPS instillation. Gavage-administered 4-PBA could improve right ventricle (RV) systolic dysfunction and dilation, plausibly by blocking ER stress.