Emphysematous Lesions, Inflammation, and Fibrosis in the Lungs of Transgenic Mice Overexpressing Platelet-Derived Growth Factor

Hoyle, Gary W.; Li, Jian; Finkelstein, Jeffrey B.; Eisenberg, Todd L.; Liu, Jing-Yao; Lasky, Joseph A.; Athas, Grace; Morris, Gilbert F.; Brody, Arnold R.

doi:10.1016/s0002-9440(10)65432-6

Cited by 126 publications

(80 citation statements)

References 45 publications

(55 reference statements)

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“…Possible additional risk factors have been identified, such as exposure to agrochemical compounds [22]. It is also recognised that overexpression of tumour necrosis factor-a and platelet-derived growth factor-b in mouse lungs produces airspace dilatation and fibrosis [23,24]. Individual genetic backgrounds may also predispose to the development of CPFE.…”

Section: Pathology and Pathogenesismentioning

confidence: 99%

The impact of emphysema in pulmonary fibrosis

Cottin¹

2013

European Respiratory Review

128

115

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Several groups have described a syndrome in which idiopathic pulmonary fibrosis (IPF) coexists with pulmonary emphysema. This comes as no surprise since both diseases are associated with a history of exposure to cigarette smoke. The syndrome of combined pulmonary fibrosis and emphysema (CPFE) is characterised by upper lobe emphysema and lower lobe fibrosis. Physiological testing of these patients reveals preserved lung volume indices contrasted by markedly impaired diffusion capacity. The incidence of CPFE remains unknown but several case series suggest that this subgroup may comprise up to 35% of patients with IPF. CPFE is a strong determinant of associated pulmonary hypertension (PH). In addition, CPFE has major effects on measures of physiological function, exercise capacity and prognosis, and may affect the results of pulmonary fibrosis trials. Further studies are needed to ascertain the aetiology, morbidity, mortality and management of the CPFE syndrome, with or without PH, and to evaluate novel therapeutic options in CPFE.

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Section: Pathology and Pathogenesismentioning

confidence: 99%

The impact of emphysema in pulmonary fibrosis

Cottin¹

2013

European Respiratory Review

128

115

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“…PDGFs accelerate inflammation and wound healing by activating mitogenesis, chemotaxis, and protein synthesis in PDGFR-positive fibroblasts and smooth muscle cells. [25][26][27] Hyperactive signaling along the PDGF/PDGFR axis also has been demonstrated in several nonmalignant disorders, such as atherosclerosis, 28,29 pulmonary fibrosis (both PDGFRa and PDGFRb), 30,31 hepatic cirrhosis (PDGFRb only), 32,33 and glomerular diseases characterized by mesangial proliferation. [34][35][36][37][38][39][40] PDGFRb-associated functions in cancer biology include pericyte recruitment and the regulation of interstitial fluid pressure in tumors, and the latter may affect the uptake of anticancer therapeutics into malignant tumors.…”

Section: The Pdgf/pdgfr Axis In Cellular Signalingmentioning

confidence: 99%

Rationale for the development of IMC‐3G3, a fully human immunoglobulin G subclass 1 monoclonal antibody targeting the platelet‐derived growth factor receptor α

Shah

Loizos²,

Youssoufian³

et al. 2010

Cancer

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A large body of evidence suggests that the platelet-derived growth factor (PDGF) family and associated receptors are potential targets in oncology therapeutic development because of their critical roles in the proliferation and survival of various cancers and in the regulation and growth of the tumor stroma and blood vessels. Several small molecules that nonspecifically target the PDGF signaling axis are in current use or development as anticancer therapies. However, for the majority of these agents, PDGF and its receptors are neither the primary targets nor the principal mediators of anticancer activity. IMC-3G3, a fully human monoclonal antibody of the immunoglobulin G subclass 1, specifically binds to the human PDGF receptor a (PDGFRa) with high affinity and blocks PDGF ligand binding and PDGFRa activation. The results of preclinical studies and the frequent expression of PDGFRa in many types of cancer and in cancer-associated stroma support a rationale for the clinical development of IMC-3G3. Currently, IMC-3G3 is being evaluated in early clinical development for patients with several types of solid malignancies. Cancer 2010;116(4 suppl):1018-26.

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“…These data reinforce the notion that the convertases may play a critical role in regulating the physiological function of PDGF-B in a paracrine and/or autocrine manner during embryonic development. On the other hand, over-expression of PDGF-B was linked to various diseases including cancer, pulmonary fibrosis and atherosclerosis (Nabel et al, 1993;Sundberg et al, 1997;Hoyle et al, 1999). In the future, it will thus be interesting to explore the role of the PC-generated processing of proPDGF-B in various pathologies, such as cancer, where upregulation of one or more convertases were previously reported (Khatib et al, 2002;Bassi et al, 2003).…”

Section: Discussionmentioning

confidence: 93%

Regulation of the stepwise proteolytic cleavage and secretion of PDGF-B by the proprotein convertases

Siegfried

Basak²,

Prichett-Pejic³

et al. 2005

Oncogene

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Platelet-derived growth factor-B (PDGF-B) is important for normal tissue growth and maintenance and its overexpression has been linked to several diseases, including cancer, fibrotic disease and atherosclerosis. Here, we show that synthesized as a precursor, proPDGF-B is converted to a mature form by proteolytic cleavage at two sites and its N-terminal cleavage is a prerequisite for processing at its C-terminus. The first cleavage occurs at residues RGRR 81 k, and the second cleavage close to residues ARPVT 190 , just before the Cterminal amino-acid sequence crucial for PDGF-B retention to cell surface. Cotransfection of a Furin-deficient cell line LoVo-C5 with proPDGF-B and different PC members revealed that Furin, PACE4, PC5, and PC7 are candidate proPDGF-B convertases. This finding is consistent with the in vitro digestions of a synthetic peptide mimicking the cleavage site of proPDGF-B. The processing of proPDGF-B is blocked by site-directed mutagenesis of the RGRR 81 k sequence and by various PC inhibitors. Mutation of the PDGF-A and/or PDGF-B convertase sites, revealed that processing of both A and B chains is required for the formation of mature PDGF-B dimers and that the processing of the B chain controls the level of secreted and matrix-bound PDGF-BB forms. Our findings emphasize the importance of the convertasedirected processing of proPDGF-B at the RGRR 81 k sequence for PDGF-B maturation and secretion. Oncogene (2005) 24, 6925-6935.

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Emphysematous Lesions, Inflammation, and Fibrosis in the Lungs of Transgenic Mice Overexpressing Platelet-Derived Growth Factor

Cited by 126 publications

References 45 publications

The impact of emphysema in pulmonary fibrosis

The impact of emphysema in pulmonary fibrosis

Rationale for the development of IMC‐3G3, a fully human immunoglobulin G subclass 1 monoclonal antibody targeting the platelet‐derived growth factor receptor α

Regulation of the stepwise proteolytic cleavage and secretion of PDGF-B by the proprotein convertases

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