Inhibition of autophagy ameliorates pulmonary microvascular dilation and PMVECs excessive proliferation in rat experimental hepatopulmonary syndrome

Abstract

Hepatopulmonary syndrome (HPS) is a defective liver-induced pulmonary vascular disorder with massive pulmonary microvascular dilation and excessive proliferation of pulmonary microvascular endothelial cells (PMVECs). Growing evidence suggests that autophagy is involved in pulmonary diseases, protectively or detrimentally. Thus, it is interesting and important to explore whether autophagy might be involved in and critical in HPS. In the present study, we report that autophagy was activated in common bile duct ligation (CBDL) rats and cultured pulmonary PMVECs induced by CBDL rat serum, two accepted in vivo and in vitro experimental models of HPS. Furthermore, pharmacological inhibition of autophagy with 3-methyladenine (3-MA) significantly alleviated pathological alterations and typical symptom of HPS in CBDL rats in vivo, and consistently 3-MA significantly attenuated the CBDL rat serum-induced excessive proliferation of PMVECs in vitro. All these changes mediated by 3-MA might explain the observed prominent improvement of pulmonary appearance, edema, microvascular dilatation and arterial oxygenation in vivo. Collectively, these results suggest that autophagy activation may play a critical role in the pathogenesis of HPS, and autophagy inhibition may have a therapeutic potential for this disease.

Galectin‐3 mediates pulmonary vascular endothelial cell dynamics via TRPC1/4 under acute hypoxia

“…[ 4 ] Autophagy acts predominantly as a prosurvival pathway in PVECs to protect them from stressful conditions. [ 5 ] Thus, the fate of PVECs under different conditions is dependent on the balance between apoptosis and autophagy.…”

Autophagy inhibitor 3-methyladenine alleviates overload-exercise-induced cardiac injury in rats

“…All samples were examined with a transmission electron microscope (H-7000FA, Japan) at an accelerating voltage of 70 kV. The quantification of autophagosomes was analyzed as previously described [10] . The autophagosomes on each slide were counted under five random fields, and the numbers of six slides were averaged for one rat.…”

“…Increasing evidence has demonstrated that autophagy contributes to various diseases, such as cancer and heart diseases [8,9] . Massive and persistent activation of autophagy may contribute to excessive cell proliferation and pathological alterations [10] . Pharmacological inhibition of autophagy after viral insults has protective effects on acute lung injury [11,12] .…”

Biphasic effects of autophagy on decompression bubble‐induced endothelial injury

“…Autophagy, a cellular lysosome‐dependent degradation process, widely participates in physiological and pathological activities of endothelial cells such as proliferation, migration and angiogenesis . The role of autophagy involved in endothelial injury in atherosclerosis, ischaemia‐reperfusion, hepatopulmonary syndrome and other diseases has been well studied . It can be induced by both physical and chemical stimuli, including shear stress, calcium and oxidative stress .…”

“…other diseases has been well studied. [12][13][14] It can be induced by both physical and chemical stimuli, including shear stress, calcium and oxidative stress. [15][16][17] Intravascular bubbles can disrupt blood flow or even occlude vessels, resulting in altered shear stress and ischaemiareperfusion injury.…”