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Bronchopulmonary Dysplasia
Published in Lourdes R. Laraya-Cuasay, Walter T. Hughes, Interstitial Lung Diseases in Children, 2019
R. Boynton Bruce, T. Allen Merritt
Neutrophil elastase is inhibited by α1protease inhibitor (α1PI) and α2 macroglobulin.5 These inhibitory proteins inactivate elastase by binding to the active site; the resulting complexes are rapidly cleared from the circulation. Macroglobulin and α1-PI do not inhibit macrophage elastase, though whole serum can supress its activity. The reason for this is not known, but may involve nonspecific effects of serum proteins (e.g., binding to the elastin substrate). The protease inhibitors are vulnerable to attack by toxic oxygen metabolites. The protein α1-PI contains sulfhydryl groups and thioethers (methionine residues) that, when altered by oxidation or alkylation, will inactivate the enzyme.5 The hydroxyl radical may be one culprit, since the elastase inhibitory capacity of α1-PI is partially protected by superoxide dismutase and catalase. These enzymes would inhibit the formation of hydroxyl radicals from superoxide and hydrogen peroxide.
Novel matrix metalloproteinase inhibitors: an updated patent review (2014 - 2020)
Published in Expert Opinion on Therapeutic Patents, 2021
Elena Lenci, Lucrezia Cosottini, Andrea Trabocchi
Macrophage elastase (MMP-12) is a particular type of MMP. It exhibits all the characteristics of other MMPs, but it is preferentially produced by macrophages infiltrating into tissues where injury or remodeling is occurring [89]. MMP-12 has a broad substrate range. In addition to its activity against elastin, MMP-12 has been shown to digest collagen type IV, fibronectin, laminin, vitronectin and plasminogen. Although it seems to be mainly involved in chronic obstructive pulmonary disorder (COPD) [90], MMP-12 has a role also in the malignant progression of several types of cancer [91], as well as other diseases including asthma, emphysema [92], acute lung injury. Thus, MMP-12 is a target of great interest in medicinal chemistry and several inhibitors have been developed over the years [93]. Recently, researchers from the Foresee Pharmaceuticals reported the synthesis and assessment of hydantoin derivatives with general formula 8 (Figure 9) that have high activity and specificity for MMP-12 (see for example compounds 8–1 and 8–2) [94].
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-12 (or macrophage elastase) release from macrophages is induced by TNFα and IL-1β [118]. Through its modulation of cytokine and chemokine activity, MMP-12 appears to regulate pulmonary neutrophil infiltration early in acute inflammation, and later is involved in the termination of this recruitment [119]. MMP-12 also displays direct bactericidal activity, attacking bacterial membranes from within the macrophage phagolysosome [120]. MMP-12 activity is increased in the lungs of people with CF, and is associated with emphysema progression [121]. A functional polymorphism in MMP-12 that leads to decreased expression (rs2276109) was found to correlate positively with lung function in CF patients [121].