Elastase-type activity associated with high density lipoproteins in human serum

Recent years have witnessed important advances in the understanding of the pathophysiology of primary pulmonary hypertension (PPH). Both genetic and mechanistic studies have succeeded in identifying new molecular pathways relevant to the process of pulmonary vascular remodelling, which underlies PPH.Mutations in the type II bone morphogenetic protein (BMP) receptor (BMPR)-II are now considered to be the genetic basis for familial PPH and y30% of cases of sporadic PPH. The identification of the relevance of the BMP pathway to the aetiology of PPH now raises many questions about the link between the BMPR-II mutant genotype and the PPH phenotype.As PPH does not develop in all subjects with BMPR-II mutations, environmental or associated genetic factors may play a crucial role. Among these, the finding of an association between PPH and the L-allelic variant of the serotonin transporter (5-HTT) gene indicates that 5-HTT, which controls smooth muscle hyperplasia, probably contributes to susceptibility to PPH or is an important modifier of the PPH phenotype.Recognition of these molecular pathways should provide insight into the pathogenesis not only of primary pulmonary hypertension, but also of secondary forms of pulmonary hypertension. This should soon lead to the development of new and more selective therapeutic approaches to pulmonary hypertension.

Section: Extracellular Matrix Remodelling: the Role Of Tenascin And Msupporting

confidence: 56%

Pathobiology of pulmonary arterial hypertension

Eddahibi

Morrell²,

d’Ortho³

et al. 2002

“…Elastin fragmentation has been shown to be an early pulmonary vascular abnormality in patients with congenital heart defects and PAH [2]. Elastinolytic activities have also been ascribed to endogenous vascular elastase [24,25]. In addition, elastinolytic properties of MMP-2 should also be taken into account [26].…”

Section: Discussionmentioning

confidence: 99%

Smooth muscle cell matrix metalloproteinases in idiopathic pulmonary arterial hypertension

Lepetit

Eddahibi²,

Fadel³

et al. 2005

128

118

Pulmonary arterial hypertension (PAH) results from persistent vasoconstriction, smooth muscle growth and extracellular matrix (ECM) remodelling of pulmonary arteries (PAs). Matrix metalloproteinases (MMPs) are matrix-degrading enzymes involved in ECM turnover, and in smooth muscle cell (SMC) and endothelial cell migration and proliferation. MMP expression and activity are increased in experimental PAH. Therefore, this study investigated whether similar changes occur in idiopathic PAH (IPAH; formerly known as primary pulmonary hypertension).Both in situ and in vitro studies were performed on PAs from patients undergoing lung transplantation for IPAH and from patients treated by lobectomy for localised lung cancer, who served as controls.In IPAH, MMP-tissue inhibitor of metalloproteinase (TIMP) imbalance was found in cultured PASMCs, with increased TIMP-1 and decreased MMP-3. MMP-2 activity was markedly elevated as a result of increases in both total MMP-2 and proportion of active MMP-2. In situ zymography and immunolocalisation showed that MMP-2 was associated with SMCs and elastic fibres, and also confirmed the MMP-3-TIMP-1 imbalance.In conclusion, the findings of this study were consistent with a role for the matrix metalloproteinase-tissue inhibitor of metalloproteinase system in pulmonary vascular remodelling in idiopathic pulmonary arterial hypertension. The matrix metalloproteinase-tissue inhibitor of metalloproteinase imbalance may lead to matrix accumulation, and increased matrix metalloproteinase-2 activity may contribute to smooth muscle cell migration and proliferation. Whether these abnormalities are potential therapeutic targets deserves further investigation.

“…These findings, in addition to those obtained in PAMs from smokers or in BAL cell extracts, suggest that three distinct types of elastase activity are liable to be present in PAMs. The first is a neutral metalloelastase-Iike activity, capable of hydrolysing SLAPN between but P 1 and P 2 Ala-Ala peptide bond but exhibiting no solubilizing elastin potential; it might be analogous to the endopeptidase found largely in cells such as lung cells and skin fibroblasts [50,51], bone marrow cells [52] or neutrophils [53] and in body fluids such as serum [33,[54][55][56][57] rheumatoid synovial fluid [58]; the complete processing of SLAPN cleavage would require the combined action of this endopeptidase and an aminopeptidase. The second type of PAM elastase is a metalloelastase capable of hydrolysing 3 Helastin; it shares several similarities with proteoglycanase also designated as stromelysin [28,39].…”

Section: Discussionmentioning

confidence: 99%

Elastase activity of bronchoalveolar cells in advanced pulmonary sarcoidosis

Mordelet-Dambrine¹,

Lafuma²,

Stanislas-Leguern³

et al. 1988

Elastase activities were investigated in bronchoalveolar lavage (BAL) cells from healthy controls (C, n = 8) and patients with untreated mediastinopulmonary sarcoidosis at different stages: I (n = 5), II (n = 7), IIIA (n = 3), IIIB (n = 4). Elastase activities (EA and ELA) were measured against a synthetic substrate, succinyl-trialanine-paranitroanilide (SLAPN) and radiolabelled ligamentum nuchae 3H insoluble elastin (specific radioactivity 3.7 MBq.mg-1). A significant increase of ELA of BAL cells was observed in patients (S III), in particular those exhibiting fibrotic roentgenographic patterns and a higher number of polymorphonuclear cells. On the contrary, EA of BAL cells showed no variation between different stages of sarcoidosis. ELA was never detected in the macrophage culture medium and appeared to be mainly associated with non-adherent macrophages, whereas EA appeared to be preferentially associated with adherent macrophages. The inhibitory profiles of ELA and EA were investigated using general proteinase inhibitors and also compounds interacting specifically with leucocyte elastase. ELA was mainly due to a serine protease, which has a sensitivity to inhibitors similar to leucocyte elastase and is increased in advanced stages of sarcoidosis. EA appears to be only slightly modified, if at all, in sarcoidosis and is probably related to the action of both a serine protease and a metalloenzyme. Thus, only ELA yields diagnostic information concerning stage III of sarcoidosis associated with a fibrotic or bullous roentgenographic pattern.