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Dysregulation of the PA/PAI System in Pulmonary Disease (ARDS and Fibrosis)
Published in Pia Glas-Greenwalt, Fibrinolysis in Disease Molecular and Hemovascular Aspects of Fibrinolysis, 2019
With the advent in the 1970s and 1980s of methods to study isolated lung cells and with the identification of the major enzymes, inhibitors, and receptors that comprise the plasmin-dependent fibrinolytic pathway,32 the specific plasminogen activators and inhibitors expressed by lung cells were largely defined. Table 1 provides a current summary of this work. Because of their easy isolation, alveolar macrophages were the first lung cell in which the various specific components of the plasminogen (plg)-dependent fibrinolytic pathway were elucidated.20,32-36 These cells remain a reasonably representative model for cellular regulation of pig-dependent proteolysis. Freshly isolated normal alveolar macrophages exhibit receptor-associated urokinase activity and express mRNA for both urokinase (u-PA) and urokinase receptor (u-PAR). The cells likely also have low-affinity receptors for plasminogen, though this has not been specifically addressed.37 No mRNA for either PAI-1 or PAI-2 is detectable. Upon adhesion in vitro and short term culture mRNA and protein for both PAI-1 and PAI-2 appear and culture supemates display u-PA inhibitory activity within 24 h.36 Macrophages obtained from smokers as well as nonsmokers show no activation of RAI expression in vivo. In contrast, in situ hybridization of lung biopsies of some patients with ARDS show PAI-1 mRNA in lung macrophages.35 Consonant with this observation, in vitro culture of macrophages in the presence of tumor necrosis factor (TNF)-a or endotoxin enhances their expression of PAI.36,38 Thus, normal macrophages exhibit a low level of pig-dependent fibrinolytic activity and this is suppressed by the appearance of PAIs following cellular stimulation by cytokines, endotoxin, and perhaps simple adhesion. Limited, highly focused fibrinolytic activity around the cell — like that observed by Kwaan and Bernik — may remain even in the presence of excess PAI and antiplasmins because of surface receptors.
The role of kidney injury biomarkers in COVID-19
Published in Renal Failure, 2022
Lianjiu Su, Jiahao Zhang, Zhiyong Peng
suPAR was recently found to be a new kidney injury biomarker. The urokinase receptor system is a key regulator of the intersection among inflammation, immunity, and coagulation [71]. SuPAR is produced when membrane-bound uPAR is cleaved in response to inflammatory stimuli [72]. It has been proven to be an early biomarker in predicting AKI following cardiac surgery and in patients in the ICU [73,74]. SuPAR levels are dramatically elevated in patients with COVID-19, implying that it may be a critical mediator of COVID-19 AKI [75,76]. Azam et al. [77] indicated that suPAR levels are predictive of in-hospital AKI and the need for dialysis in patients with COVID-19. It may have a role in defense mechanisms and fibrinolysis, and low levels in severe patients may be related to poor prognosis in the early period [78]. A clinical trial involving 767 participants was carried out to investigate the role of suPAR in adult patients with COVID-19 (NCT04590794), and UPAR has been identified as a predictor of disease progression biomarkers in COVID-19 [79, 80]. Rovina and colleagues claimed that suPAR could be an early predictor of severe respiratory failure in patients with COVID-19 [75]. Moreover, Oulhaj et al. [75] indicated that suPAR has excellent prognostic utility in predicting severe complications in hospitalized patients with COVID-19. Future studies should identify the role of suPAR as a key component of the pathophysiology of AKI in COVID-19.
Cysteine cathepsins as therapeutic targets in inflammatory diseases
Published in Expert Opinion on Therapeutic Targets, 2020
Matej Vizovišek, Eva Vidak, Urban Javoršek, Georgy Mikhaylov, Andreja Bratovš, Boris Turk
There are numerous cellular and in vivo studies, where secretion of cathepsins from immune and tumor cells was shown to lead to tumor progression [31]. However, this is not limited only to secreted cathepsins, as demonstrated for their role in epithelial-to-mesenchymal transition. Accordingly, the upregulation of cathepsins B and X in MCF7 cells resulted in a decrease of E-cadherin, mainly due to their proteolytic action [55]. Moreover, upon release, cathepsin B can interact with NLRP3 inflammasome which leads to activation of caspase-1 and pro-IL-1β processing. This acts as an important enhancer of IL-17 production in CD 4+ T cells and is a detrimental factor in tumor relapse [56]. Nevertheless, it seems that more important cancer-related roles of cathepsins are the cleavage of cell-cell junctions [57], extracellular matrix degradation [58] and proteolytic processing and shedding of cell surface receptors and cell adhesion molecules [44,59]. In addition, cathepsins are involved in the activation of other tumor-associated proteases, although this evidence is mostly circumstantial and primarily based on in vitro studies. Examples of this are cathepsin B, which was reported to be involved in uPA/uPAR (urokinase-type plasminogen activator/urokinase receptor) signaling, and cathepsin L, which has a role in the activation of MMP1 (matrix metalloproteinase) and MMP3 [60]. Consequently, cathepsins could be important for the inflammatory cross-talk between different protease families.
Exploitation of receptor tyrosine kinases by viral-encoded growth factors
Published in Growth Factors, 2018
The unique receptor profile of ORFV VEGF-E variants has been exploited to dissect VEGFR2 signalling pathways in endothelial cells. Selective activation by VEGF-E demonstrated the role of VEGFR2 in activation of ERK, Akt, PLCγ and endothelial cell proliferation and tube formation (Kawamura et al., 2008; Grummer et al., 2009; Cudmore et al., 2012). The role of VEGFR2 in eNOS expression, NO release, and vessel vasodilation was also demonstrated with VEGF-E (Kroll & Waltenberger, 1999; Ahmad et al., 2006; Cudmore et al., 2006). VEGF-E-induced pro-urokinase-type plasminogen activator expression, urokinase receptor trafficking and fibrinolytic activity confirmed a role for VEGFR2 in endothelial cell migration (Prager et al., 2004; Poettler et al., 2012). Studies with VEGF-E also illustrated that VEGFR2 activation of MAPK phosphatase-1 leads to dephosphorylation of ERK and p38MAPK and suppression of endothelial cell migration (Kinney et al., 2008). As selected VEGF-E variants bind NRP1, they have also proved useful in defining the influence of this co-receptor on VEGFR2-mediated activities. Activation of the VEGFR2-NRP1 complex has highlighted the role of NRP1 in sprouting angiogenesis in embryonic stem cells, formation of branching pericyte-coated vessels in subcutaneous matrigel plugs in mice and sprouting of intersegmental vessels in zebrafish (Kawamura et al., 2008). The endothelial signalling pathways induced by the other PPV VEGF-Es and megalocytivirus VEGFs have not yet been examined.