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Am J Physiol Lung Cell Mol Physiol 295: L789-L799, 2008. First published September 5, 2008; doi:10.1152/ajplung.90306.2008
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High levels of hyaluronan in idiopathic pulmonary arterial hypertension

Metin Aytekin,1 Suzy A. A. Comhair,1 Carol de la Motte,1 Sudip K. Bandyopadhyay,1 Carol F. Farver,3 Vincent C. Hascall,2 Serpil C. Erzurum,1,4 and Raed A. Dweik1,4

Departments of 1Pathobiology and 2Biomedical Engineering, Lerner Research Institute, and Departments of 3Pathology and 4Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, Cleveland, Ohio

Submitted 9 May 2008 ; accepted in final form 29 August 2008

Hyaluronan (HA), a large glycosaminoglycan found in the ECM, has major roles in lung and vascular biology and disease. However, its role in idiopathic pulmonary arterial hypertension (IPAH) is unknown. We hypothesized that HA metabolism is abnormal in IPAH. We measured the plasma levels of HA in IPAH and healthy individuals. We also evaluated HA synthesis and the expression of HA synthases and hyaluronidases in pulmonary artery smooth muscle cells (PASMCs) from explanted lungs. Plasma HA levels were markedly elevated in IPAH compared with controls [HA (ng/ml, mean ± SD): IPAH 325 ± 80, control 28 ± 9; P = 0.02]. In vitro, unstimulated IPAH PASMCs produced high levels of HA compared with control cells [HA in supernatant (µg/ml, mean ± SD): IPAH 12 ± 2, controls 6 ± 0.9; P = 0.04]. HA levels were also higher in IPAH PASMC lysates. The increased HA was biologically relevant as shown by tissue staining and increased HA-specific binding of mononuclear cells to IPAH compared with control PASMCs [number of bound cells x 104 (mean ± SD): IPAH 9.5 ± 3, control 3.0 ± 1; P = 0.01]. This binding was abrogated by the addition of hyaluronidase. HA synthase-2 and hyaluronidase-2 were predominant in control and IPAH PASMCs. Interestingly, the expressions of HA synthase-2 and hyaluronidase-2 were ~2-fold lower in IPAH compared with controls [HA synthase-2 (relative expression mean ± SE): IPAH 4.3 ± 0.02, control 7.8 ± 0.1; P = 0.0004; hyaluronidase-2 (relative expression mean ± SE): IPAH 4.2 ± 0.06, control 7.6 ± 0.07; P = 0.008]. Thus patients with IPAH have higher circulating levels of HA, and PASMCs derived from IPAH lungs produce more HA compared with controls. This is associated with increased tissue levels and increased binding of inflammatory cells suggesting a role for HA in remodeling and inflammation in IPAH.

hyaluronidase; lung; remodeling


Address for reprint requests and other correspondence: R. A. Dweik, Dept. of Pulmonary and Critical Care Medicine, Respiratory Institute, Desk A-90, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195 (e-mail: dweikr{at}ccf.org)






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