Abstract:Chronic pulmonary hypertension is associated with extensive structural remodeling of the pulmonary arterial bed. The structural changes in the arterial walls include increased production of extrace~lular matrix components and smooth muscle cell hypertrophy, changes that have been similarly induced by transforming growth factor-f, (TGF-ft) in culture. In the present study, experiments were performed to determine whether TGF-ft is present in sheep lung lymph, and whether TGF-fi levels were altered in an animal m… Show more
“…The increased activation of TGF-β1 signaling in PAs was reported in idiopathic PAH patients (52) and in different PAH animal models (53,54), and inhibition of the TGF-β1 receptor activin receptorlike kinase 1 prevents the development of PAH (55). Similarly, we observed elevated TGF-β1 signaling in the PAs of hypoxia-induced PAH models.…”
Section: Ep3a/b Modulates Hypoxia-induced Mmp-2/tgf-β1 Activation By supporting
“…The increased activation of TGF-β1 signaling in PAs was reported in idiopathic PAH patients (52) and in different PAH animal models (53,54), and inhibition of the TGF-β1 receptor activin receptorlike kinase 1 prevents the development of PAH (55). Similarly, we observed elevated TGF-β1 signaling in the PAs of hypoxia-induced PAH models.…”
Section: Ep3a/b Modulates Hypoxia-induced Mmp-2/tgf-β1 Activation By supporting
“…TGF-β is one of the most potent regulators of connective tissue synthesis and controls deposition of profibrotic extracellular matrix protein. It plays a role in lung tissue remodeling following injury (39), and despite its crucial role in tissue repair, a fine bal- ance is required, as increased levels of TGF-β or its receptors have been shown to result in severe pulmonary fibrosis in rat models (40). A genetic comprehensive study has indicated that TGF-β gene modifies lung disease severity in CF (41).…”
Progressive pulmonary disease and infections with Pseudomonas aeruginosa remain an intractable problem in cystic fibrosis (CF). At the cellular level, CF is characterized by organellar hyperacidification, which results in altered protein and lipid glycosylation. Altered pH of the trans-Golgi network (TGN) may further disrupt the protein processing and packaging that occurs in this organelle. Here we measured activity of the major TGN endoprotease furin and demonstrated a marked upregulation in human CF cells. Increased furin activity was linked to elevated production in CF of the immunosuppressive and tissue remodeling cytokine TGF-β and its downstream effects, including macrophage deactivation and augmented collagen secretion by epithelial cells. As furin is responsible for the proteolytic processing of a range of endogenous and exogenous substrates including growth factors and bacterial toxins, we determined that elevated furin-dependent activation of exotoxin A caused increased cell death in CF respiratory epithelial cells compared with genetically matched CF transmembrane conductance regulator-corrected cells. Thus elevated furin levels in CF respiratory epithelial cells contributes to bacterial toxin-induced cell death, fibrosis, and local immunosuppression. These data suggest that the use of furin inhibitors may represent a strategy for pharmacotherapy in CF.
“…It is possible that, like other serine proteinases (32)(33)(34), EVE releases growth factors, such as basic fibroblast growth factor or transforming growth factor-,B, from the extracellular matrix and activates them. These growth factors (35,36) among others (37,38) have been implicated in pulmonary (35) and systemic vascular pathology (36 …”
We showed previously a cause and effect relationship between increased activity of an endogenous vascular elastase (EVE) and experimentally induced pulmonary hypertension in rats. We now report the isolation and characterization of EVE. Degenerate oligonucleotides synthesized to homologous sequences in serine elastases were used in a PCR with rat pulmonary artery (PA) cDNA. The PCR product hybridized to a 1.2-kb mRNA and the intensity of hybridization was threefold increased in RNA from rat hypertensive PA at a timepoint when EVE activity was increased. The PCR product was used to screen a cDNA library and sequences obtained encoded rat adipsin. We then used immunoaffinity to purify EVE. An antibody to the elastin-binding protein was used to remove this competitor of elastase from the PA extract and the elastolytic activity increased 100-fold. The enzyme was purified using an antibody that recognizes NH2-terminal sequences of serine proteinases and the eluate was further purified using an antibody raised against recombinant adipsin. A single band at 20 kD immunoreactive with the adipsin antibody was resolved as an active enzyme on an elastin substrate gel. Immunogold labeling with an antibody to an adipsin peptide sequence localized EVE to PA smooth muscle cells. This is the first isolation of EVE; it appears to be a novel enzyme related to the serine proteinase adipsin originally found in adipose tissue. (J.
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