Abstract
We previously reported an altered hyaluronan (HA) metabolism in idiopathic pulmonary arterial hypertension (IPAH) lung tissue and cultured smooth muscle cells. Hyaluronan was present in the smooth muscle cell layer surrounding the pulmonary vasculature and in plexigenic lesions. Additionally, cultured pulmonary artery smooth muscle cells produced spontaneous HA "cable" structures, without additional stimuli, that were leukocyte-adhesive. We now present evidence that the HA that accumulates in IPAH plexigenic lesions is a pathological form of HA in which heavy chains (HCs) from the serum-derived proteoglycan inter-α-inhibitor are covalently attached to the HA backbone to form a pathological HC-HA complex. CD45-positive leukocytes were identified within these HC-HA matrices. Elevated mRNA levels of the enzyme that transfers HCs to HA, known as tumor necrosis factor-stimulated gene 6, were detected in IPAH lung tissue.
Highlights
Hyaluronan metabolism is altered in idiopathic pulmonary arterial hypertension lung tissue
We present evidence that the HA that accumulates in idiopathic pulmonary arterial hypertension (IPAH) plexigenic lesions is a pathological form of HA in which heavy chains (HCs) from the serum-derived proteoglycan inter-␣-inhibitor are covalently attached to the HA backbone to form a pathological HC-HA complex
This experiment was repeated with two other control and IPAH lung tissues from different human subjects with similar effects, demonstrating a 4.37-fold increase in HC-HA in IPAH lung tissue compared with control lung (p ϭ 0.030)
Summary
Hyaluronan metabolism is altered in idiopathic pulmonary arterial hypertension lung tissue. We previously reported an altered hyaluronan (HA) metabolism in idiopathic pulmonary arterial hypertension (IPAH) lung tissue and cultured smooth muscle cells. We present evidence that the HA that accumulates in IPAH plexigenic lesions is a pathological form of HA in which heavy chains (HCs) from the serum-derived proteoglycan inter-␣-inhibitor are covalently attached to the HA backbone to form a pathological HC-HA complex. Regions is an abnormal form of HA characterized by its covalent substitution with heavy chains (HCs) from inter-␣-inhibitor (I␣I). This abnormal form of HA (i.e. HC-HA) is known to increase the avidity of leukocytes to HA matrices
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