Matrix metalloproteinases (MMPs) are zinc-dependent endoproteases responsible for the metabolism of extracellular matrix (ECM). MMPs can degrade the various ECM components as a variety of non-ECM ...molecules. Hyperactivity of MMPs and improper regulation or inhibition could lead to certain disorders, like non-healing chronic wounds. In chronic wounds, unlike in acute ones, there are always higher levels of MMPs due to the accompanying inflammation. Different proteases are responsible for this condition; nonetheless, blocking MMPs can help restore the wound's healing ability. The level of MMPs can help indicate the prognosis of chronic wounds. In some cases, the healing process is delayed by microbial wound infections. Bacterial proteases may up-regulate the levels of MMPs produced by host cells. That means that both host MMPs as proteases secreted by the infecting bacteria need to be targeted to increase the healing capacity of the wound. MMPs activity modulating treatments by superabsorbent polymer dressings can improve healing rates of chronic wounds. The main goal of this review was presentation the specific role of metalloproteinases in the pathology and therapy of hard-to-heal wounds.
In many organs, hypoxic cell death triggers sterile neutrophilic inflammation via IL-1R signaling. Although hypoxia is common in airways from patients with cystic fibrosis (CF), its role in ...neutrophilic inflammation remains unknown. We recently demonstrated that hypoxic epithelial necrosis caused by airway mucus obstruction precedes neutrophilic inflammation in Scnn1b-transgenic (Scnn1b-Tg) mice with CF-like lung disease.
To determine the role of epithelial necrosis and IL-1R signaling in the development of neutrophilic airway inflammation, mucus obstruction, and structural lung damage in CF lung disease.
We used genetic deletion and pharmacologic inhibition of IL-1R in Scnn1b-Tg mice and determined effects on airway epithelial necrosis; levels of IL-1α, keratinocyte chemoattractant, and neutrophils in bronchoalveolar lavage; and mortality, mucus obstruction, and structural lung damage. Furthermore, we analyzed lung tissues from 21 patients with CF and chronic obstructive pulmonary disease and 19 control subjects for the presence of epithelial necrosis.
Lack of IL-1R had no effect on epithelial necrosis and elevated IL-1α, but abrogated airway neutrophilia and reduced mortality, mucus obstruction, and emphysema in Scnn1b-Tg mice. Treatment of adult Scnn1b-Tg mice with the IL-1R antagonist anakinra had protective effects on neutrophilic inflammation and emphysema. Numbers of necrotic airway epithelial cells were elevated and correlated with mucus obstruction in patients with CF and chronic obstructive pulmonary disease.
Our results support an important role of hypoxic epithelial necrosis in the pathogenesis of neutrophilic inflammation independent of bacterial infection and suggest IL-1R as a novel target for antiinflammatory therapy in CF and potentially other mucoobstructive airway diseases.
Whereas cigarette smoking remains the main risk factor for emphysema, recent studies in β-epithelial Na(+) channel-transgenic (βENaC-Tg) mice demonstrated that airway surface dehydration, a key ...pathophysiological mechanism in cystic fibrosis (CF), caused emphysema in the absence of cigarette smoke exposure. However, the underlying mechanisms remain unknown. The aim of this study was to elucidate mechanisms of emphysema formation triggered by airway surface dehydration. We therefore used expression profiling, genetic and pharmacological inhibition, Foerster resonance energy transfer (FRET)-based activity assays, and genetic association studies to identify and validate emphysema candidate genes in βENaC-Tg mice and patients with CF. We identified matrix metalloproteinase 12 (Mmp12) as a highly up-regulated gene in lungs from βENaC-Tg mice, and demonstrate that elevated Mmp12 expression was associated with progressive emphysema formation, which was reduced by genetic deletion and pharmacological inhibition of MMP12 in vivo. By using FRET reporters, we show that MMP12 activity was elevated on the surface of airway macrophages in bronchoalveolar lavage from βENaC-Tg mice and patients with CF. Furthermore, we demonstrate that a functional polymorphism in MMP12 (rs2276109) was associated with severity of lung disease in CF. Our results suggest that MMP12 released by macrophages activated on dehydrated airway surfaces may play an important role in emphysema formation in the absence of cigarette smoke exposure, and may serve as a therapeutic target in CF and potentially other chronic lung diseases associated with airway mucus dehydration and obstruction.
Gene expression profiles of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) were evaluated in peripheral blood leukocytes of children with nonalcoholic fatty liver disease ...(NAFLD). Gene expression patterns were correlated with their plasma protein counterparts, systemic parameters of liver injury, and selected markers of inflammation. The MMP-2, MMP-9, MMP-12, MMP-14, TIMP-1, TIMP-2, TGF-β, and IL-6 transcripts levels were tested by the real-time PCR. Plasma concentrations of MMP-9, TIMP-1, MMP-9/TIMP-1 ratio, MMP-2/TIMP-2 ratio, sCD14, leptin, resistin, IL-1 beta, and IL-6 and serum markers of liver injury were estimated by ELISA. The MMP-9, TIMP-2 expression levels, plasma amounts of MMP-9, TIMP-1, and the MMP-9/TIMP-1 ratio were increased in children with NAFLD. Concentrations of AST, ALT, GGT, and leptin were elevated in serum patients with NAFLD, while concentration of other inflammatory or liver injury markers was unchanged. The MMP-2 and MMP-9 levels correlated with serum liver injury parameters (ALT and GGT concentrations, respectively); there were no other correlations between MMP/TIMP gene expression profiles, their plasma counterparts, and serum inflammatory markers. Association of MMP-2 and MMP-9 expression with serum liver injury parameters (ALT, GGT) may suggest leukocyte engagement in the early stages of NAFLD development which possibly precedes subsequent systemic inflammatory responses.
Nuclear IRS-1 and cancer Reiss, Krzysztof; Del Valle, Luis; Lassak, Adam ...
Journal of cellular physiology,
August 2012, Letnik:
227, Številka:
8
Journal Article
Abstract
Recent evidence points at the role that human endogenous retroviruses (HERVs) may play through the activation of genes integrated across the human genome. Although a variety of ...genetic/epigenetic mechanisms maintain most HERVs silenced, independent environmental stimuli including infections may transactivate endogenous elements favoring pathogenic conditions. Several studies associated exposures to
Mycobacterium avium
subsp.
paratuberculosis
(MAP) with increased anti-MAP seroreactivity in T1D patients. Here, we assessed humoral responses against HERV envelope antigens (HERV-K
Env
and HERV-W
Env
) and four MAP-derived peptides with human homologs in distinct populations: Sardinian children at T1D risk (rT1D) (n = 14), rT1D from mainland Italy (n = 54) and Polish youths with T1D (n = 74) or obesity unrelated to autoimmunity (OB) (n = 26). Unlike Sardinian rT1D, youths displayed increased anti-HERV-W
Env
Abs prevalence compared to age-matched OB or healthy controls (24.32 vs. 11.54%,
p
= 0.02 for Polish T1D/OB and 31.48 vs. 11.90%,
p
= 0.0025 for Italian rT1D). Anti-HERV-K
Env
responses showed variable trends across groups. A strong correlation between Abs levels against HERV-W
Env
and homologous peptides was mirrored by time-related Abs patterns. Elevated values registered for HERV-W
Env
overlaped with or preceded the detection of T1D diagnostic autoantibodies. These results support the hypothesis of MAP infection leading to HERV-W antigen expression and enhancing the production of autoantibodies in T1D.
Matrix metalloproteinases (MMPs) are calcium-dependent zinc-containing endo-peptidases engaged in many biological processes including adipogenesis, angiogenesis, and tissue remodeling. Fat tissue ...infiltration by peripheral leukocytes plays an important role in transition of fat tissue residual, non-inflammatory status into the pro-inflammatory one, resulting in fat tissue inflammation and expansion as well as production of many mediators like adipokines and cytokines. The aim of this study was to investigate the expression of MMPs, their endogenous tissue inhibitors (TIMPs), and selected inflammatory mediators in leukocytes and plasma of children with simple obesity to find their associations with obesity-related phenotypes.
Twenty-six overweight/obese children and twenty-three healthy volunteers participated in the study. The leukocyte mRNA expression levels of
,
,
,
,
, and IL
were analyzed by the real time quantitative PCR. Plasma MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios as well as the concentrations of MMP-9, TIMP-1, IL-1 beta, IL-6, TNF- alpha, leptin and resistin were tested by ELISA assays. Gelatin zymography was used to assess the activity of the leukocyte MMPs proteins.
The obese children showed the following: a) increased expression of leukocyte
and slight elevation (close to statistical significance) of leukocyte
(
= 0.054), the decline in
, b) elevation of plasma MMP-9, leptin, and MMP9/TIMP1 ratio, c) reduced expression of plasma TNF-alpha and MMP-2/TIMP-2 ratio. Several negative correlations were found:
vs. ALT (r = -0.536), AST (r = -0.645) and TTG (r = -0.438),
vs. GGTP (r = -0.815), and
vs. TTG (r = -0.488), leptin vs. ALT (r = -0.569), MMP-9 vs. total cholesterol (r = -0.556). The only positive correlation was that of plasma leptin level vs. GGTP (r = 0.964).
At the beginning of obesity development (children), possibly compensatory reactions prevail, reflected here by an increase in the expression of leukocyte MMPs inhibitor
, decrease in the level of leukocyte
and plasma MMP-2, MMP2/TIMP-2 ratio, low plasma TNF-alpha and negative correlations between the expression of
and liver (AST, ALT) or fat (TTG) inflammatory markers.
Chronic obstructive pulmonary disease is a leading cause of death worldwide, but its pathogenesis is not well understood. Previous studies have shown that airway surface dehydration in ...beta-epithelial Na(+) channel (betaENaC)-overexpressing mice caused a chronic lung disease with high neonatal pulmonary mortality and chronic bronchitis in adult survivors.
The aim of this study was to identify the initiating lesions and investigate the natural progression of lung disease caused by airway surface dehydration.
Lung morphology, gene expression, bronchoalveolar lavage, and lung mechanics were studied at different ages in betaENaC-overexpressing mice.
Mucus obstruction in betaENaC-overexpressing mice originated in the trachea in the first days of life and was associated with hypoxia, airway epithelial necrosis, and death. In surviving betaENaC-overexpressing mice, mucus obstruction extended into the lungs and was accompanied by goblet cell metaplasia, increased mucin expression, and airway inflammation with transient perinatal increases in tumor necrosis factor-alpha and macrophages, IL-13 and eosinophils, and persistent increases in keratinocyte-derived cytokine (KC), neutrophils, and chitinases in the lung. betaENaC-overexpressing mice also developed emphysema with increased lung volumes, distal airspace enlargement, and increased lung compliance.
Our studies demonstrate that airway surface dehydration is sufficient to initiate persistent neutrophilic airway inflammation with chronic airways mucus obstruction and to cause transient eosinophilic airway inflammation and emphysema. These results suggest that deficient airway surface hydration may play a critical role in the pathogenesis of chronic obstructive pulmonary diseases of different etiologies and serve as a target for novel therapies.
Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play an important role in cardiovascular remodeling. The aim of the study was to analyze MMP/TIMP genes expression in peripheral ...blood leukocytes of 80 hypertensive children (15.1 ± 2.0 years) in comparison with age-matched 78 normotensive children (14.6 ± 2.0 years; n.s.). TIMP and MMP expression in peripheral blood leukocytes was assessed by quantitative real-time PCR. Hypertensive children independently of age, sex, and body mass index had greater expression of MMP-2 than normotensive controls (p = 0.0001). Patients with left ventricular hypertrophy had greater expression of MMP-14 than patients with normal left ventricular mass (p = 0.006) and TIMP-2 expression correlated with carotid wall cross-sectional area (p = 0.03; r = 0.238). MMP-14 expression correlated with BMI-SDS (p = 0.001; r = 0.371), waist circumference-SDS (p = 0.016; r = 0.290), hsCRP (p = 0.003; r = 0.350), serum HDL-cholesterol (p = 0.008; r = -0.304), and serum uric acid (p = 0.0001; r = 0.394). In conclusion, hypertensive adolescents presented significant alterations of MMP/TIMP expression pattern in comparison with normotensive peers. Moreover, altered MMP/TIMP expression was associated with hypertensive target organ damage and metabolic abnormalities.
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