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α1-Antitrypsin: Structure, Function, Physiology
Published in Andrzej Mackiewicz, Irving Kushner, Heinz Baumann, Acute Phase Proteins, 2020
The net functional activity of α1-AT in complex biological fluids may be modified by several factors. First, the reactive-site methionine of α1-AT may be oxidized and thereby rendered inactive as an elastase inhibitor. The relationship of oxidation to the net biological activity of α1-AT in vivo is not fully understood. However, α1-AT is oxidatively inactivated in vitro by activated neutrophils46,47 and by oxidants released by alveolar macrophages of cigarette smokers.48 α1-AT purified from the bronchoalveolar lavage fluid of smokers has a reduced association rate constant for neutrophil elastase.49 Second, the functional activity of α1-AT may be modified by proteolytic inactivation. A metalloproteinase secreted by mouse macrophages,50 neutrophil collagenase,51,52 neutrophil gelatinase,52–54 interstitial collagenase,55 stromelysin,56 thiol proteinase cathepsin L,57 and pseudomonas elastase58 represent examples of proteinases shown to cleave and inactivate α1-AT. Moreover, secreted products of rabbit alveolar macrophages have been shown to modify α1-AT functional activity by proteolytic inactivation.59 Interaction of elastase and other serine proteases with components of extracellular matrix, specifically the glycosaminoglycans heparin and vitronectin, may affect the rate of inactivation of these proteases by α1-AT.60
Biochemistry and Physiology of Mammalian Collagenases
Published in Marcel E. Nimni, Collagen, 1988
George P. Stricklin, Margaret S. Hibbs
Table 1 presents a summary of the molecular weight estimates for several vertebrate collagenases. It appears that the most reliable estimates are obtained from electrophoresis on SDS-PAGE as the behavior of these enzymes in gel filtration matrices is anomalous.24 Electrophoresis of enzyme secreted by human fibroblasts reveals characteristic doublet bands of 60 and 55 kd, respectively.24 Trypsin-activated forms of approximately 50 and 45 kd have been identified as products of the 60 and 55 kd proteins, respectively.24 More recent determinations give slightly lower estimates, generally in the range of 57 and 52 kd; however, the 5 kd differential remains. Other characterized human collagenases (gingival,31 macrophage32) appear to share these molecular weight patterns, as do the enzymes derived from rabbit synovial cells.27 Although a variety of molecular weight estimates have been offered for human neutrophil collagenase, they all appear to differ from that of the fibroblast counterpart.33–35Figure 2 illustrates the electrophoretic pattern of both human fibroblast and human neutrophil collagenase.
Epithelial damage in the cystic fibrosis lung: the role of host and microbial factors
Published in Expert Review of Respiratory Medicine, 2022
Arlene M. A. Glasgow, Catherine M. Greene
MMP-2 (or gelatinase A) was found elevated in CF BALF by Bergin and colleagues [107]. Treatment of the Calu-3 cell line with anti-MMP-2 antibodies increased CFTR chloride channel activity, suggesting MMP-2 can regulate ion transport [108]. MMP-8 (or neutrophil collagenase) is highly expressed in neutrophils and increased in CF BALF [109]. As well as having a role in wound repair [110], MMP-8 is involved in the generation of the neutrophil chemoattractant proline-glycine-proline (PGP) from collagen cleavage [111]. This peptide is increased in CF sputum relative to healthy controls and is high during exacerbation [111]. PGP is normally degraded by leukotriene A4 hydrolase (LTA4H) in order to limit its effects, but the expected increase in LTA4H is not observed in the CF airway, potentially contributing to airway neutrophilia [112].
aMMP-8 point-of-care - diagnostic methods and treatment modalities in periodontitis and peri-implantitis
Published in Expert Opinion on Therapeutic Targets, 2023
Hanna Lähteenmäki, Tommi Pätilä, C Pirjo Pärnänen, Ismo Räisänen, Taina Tervahartiala, Shipra Gupta, Timo Sorsa
Matrix metalloproteinase-8 also called collagenase-2 or neutrophil collagenase is one of the main key biomarkers in the breakdown of connective tissue in periodontitis and peri-implantitis [1,67,68]. Many studies have shown that the release and activity of MMP-8 are increased in oral chronic inflammation [69,70]. In humans MMP-8 can be found and examined for its total, latent and active forms [24]. The level of aMMP-8 (- not the latent MMP-8) can be used as a biomarker to determine the current state of oral tissue health, to assess the state of inflammation and to predict the future clinical status of the periodontium and peri-implant tissues. aMMP-8 enzyme level can be measured from oral fluids, including mouth rinse and GCF/PISF samples [1,26,31,71–74].
The collagenases: are they tractable targets for preventing cartilage destruction in osteoarthritis?
Published in Expert Opinion on Therapeutic Targets, 2022
Tuomo Karila, Taina Tervahartiala, Beniamin Cohen, Timo Sorsa
The collagenases MMP-1 and MMP-13 are rate-limiting in the process of collagen degradation. MMP-1 is produced primarily by synovial cells, and MMP-13 is a product of chondrocytes. However, MMP-13 also degrades the proteoglycan molecule aggrecan, therefore playing a dual role in ECM destruction [9]. It cleaves aggrecan in the IGD at the same site [82]. Although, MMP-1 has also ability to cleave aggrecan [83]. Then again, MMP-8 has demonstrated to have in vitro aggrecanase activity [84]. Despite, MMP-8 is considered as a neutrophil collagenase, it has been found in OA lesions without neutrophils. Therefore, especially in response to proinflammatory cytokines (TNF-α, IL-1β) chondrocytes or synovial cells, are de-novo capable of its production [73].