The role of low molecular weight hyaluronan in the pathogenesis of monocrotaline‐induced pulmonary hypertension

Abstract

Extracellular matrix degradation products, such as low molecular weight hyaluronan (LMW HA), have been shown to stimulate the innate inflammatory response and could play a fundamental role in the pathogenesis of pulmonary hypertension (PH). The role of LMW HA in experimental, monocrotaline (MCT)‐induced PH was investigated in Fisher 344 rats. Twenty‐four days after MCT injection (0.7mg/kg), right ventricular systolic pressure was markedly elevated in MCT treated animals (62.9 ± 5.6 mmHg) when compared to no MCT controls (24.3 ± 0.8 mmHg). Quantification of total lung HA by ELISA revealed increased HA in MCT treated animals when compared to controls (248+/−71 versus 154+/−17 ng HA/mg dry lung). This data was supported by histological analysis of lung sections, which show elevated levels of HA in association with regions of vascular occlusion as well as with inflammatory cell infiltrates. Molecular weight analysis of lung‐derived HA by agarose gel electropheresis illustrated that MCT‐induced PH is associated with an accumulation of LMW HA (>5×105 Da) and a corresponding decrease in high molecular weight HA (∼4×106 Da). Gene expression analysis of the hyaluronan synthase (HAS) genes revealed that MCT‐induced PH corresponds with increased expression of HAS1 and HAS2 (1.67+/−0.14 and 3.37+/−0.55 fold increases vs. normal, respectively) and a decrease in HAS3 expression (4.86+/−0.16 fold decrease vs. normal).