Roles of apoptosis and inflammation in a rat model of acute lung injury induced right ventricular dysfunction

Abstract

Aim: The effect of intratracheal lipopolysaccharide (LPS) instillation on right ventricular dysfunction in rats was studied with the aim of exploring underlying mechanisms.

Main methods: A single dose of LPS (10 mg/kg) or an equal volume of saline was instilled intratracheally and lung injury evaluated using histopathologic scoring and wet/dry (W/D) weight ratio at 6 or 12 h post-administration. Besides, serum atrial natriuretic peptide (ANP) was detected using an enzyme-linked immunosorbent assay (ELISA) and right ventricle β-myosin heavy chain (β-MHC) presence was examined using reverse transcription polymerase chain reaction (RT-PCR). Echocardiography examined pulmonary artery acceleration time (PAAT), right ventricular free wall thickness (RVFWT), tricuspid annular plane systolic excursion (TAPSE), and right ventricular end-diastolic diameter (RVEDD). In addition, right ventricular TUNEL staining and Western blots of Bax and Bcl-2 were performed. Right ventricle and left ventricle caspases-3, -8, and -9 activity were examined using fluorometric assay. Finally, right ventricle myeloperoxidase (MPO) neutrophil staining, and right ventricle and plasma cytokines TNF-α, IL-1β, IL-6 detection was performed.

Key findings: Histopathologic lung injury and increased W/D weight ratio was seen at 6 h after LPS intratracheal instillation, along with increased ANP, but not β-MHC. Pulmonary hypertension was indicated by decreased PAAT at 6 h post-exposure. Right ventricular systolic dysfunction and dilation were observed at 12 h post-exposure, as indicated by a significant decrease of TAPSE and increase of RVEDD. Of note, the procedure led to an increased right ventricle TUNEL positive cardiomyocytes, an increased Bax/Bcl-2 ratio, and increased right and left ventricle caspases-3, -8, and -9 activity as early as 6 h post-exposure, which was paralleled by increased right ventricle MPO staining and increased expression of right ventricle and serum cytokines TNF-α, IL-1β, and IL-6.

Significance: As well as acute lung injury, a single dose of LPS intratracheally instilled can induce pulmonary hypertension at 6 h post-exposure, with obvious right ventricular systolic dysfunction and right ventricular dilation present at 12 h post-exposure, possibly via cardiomyocytes apoptosis and inflammation.

Keywords: Acute lung injury; Apoptosis; Echocardiography; Inflammation; LPS; Right ventricular dysfunction.