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2.
PLoS One ; 15(4): e0231202, 2020.
Article in English | MEDLINE | ID: mdl-32271823

ABSTRACT

OBJECTIVE: Monoclonal antibody derivatives are promising drugs for the treatment of various diseases due to their high matrix metalloproteinases (MMP) active site specificity. We studied the effects of a novel antibody, SDS3, which specifically recognizes the mature active site of MMP9/2 during ventricular remodeling progression in a mouse model of chronic volume overload (VO). METHODS: VO was induced by creating an aortocaval fistula (ACF) in 10- to 12-week-old C57BL male mice. The VO-induced mice were treated with either vehicle control (PBS) or with SDS3 twice weekly by intraperitoneal (ip) injection. The relative changes in cardiac parameters between baseline (day 1) and end-point (day 30), were evaluated by echocardiography. The effects of SDS3 treatment on cardiac fibrosis, cardiomyocyte volume, and cardiac inflammation were tested by cardiac staining with Masson's trichrome, wheat Germ Agglutinin (WGA), and CD45, respectively. Serum levels of TNFα and IL-6 with and without SDS3 treatment were tested by ELISA. RESULTS: SDS3 significantly reduced cardiac dilatation, left ventricular (LV) mass, and cardiomyocyte hypertrophy compared to the vehicle treated animals. The antibody also reduced the heart-to-body weight ratio of the ACF animals to values comparable to those of the controls. Interestingly, the SDS3 group underwent significant reduction of cardiac inflammation and pro-inflammatory cytokine production, indicating a regulatory role for MMP9/2 in tissue remodeling, possibly by tumor necrosis factor alpha (TNFα) activation. In addition, significant changes in the expression of proteins related to mitochondrial function were observed in ACF animals, these changes were reversed following treatment with SDS3. CONCLUSION: The data suggest that MMP9/2 blockage with SDS3 attenuates myocardial remodeling associated with chronic VO by three potential pathways: downregulating the extracellular matrix proteolytic cleavage, reducing the cardiac inflammatory responses, and preserving the cardiac mitochondrial structure and function.


Subject(s)
Antibodies, Blocking/pharmacology , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Matrix Metalloproteinase Inhibitors/pharmacology , Ventricular Remodeling/drug effects , Animals , Chronic Disease , Dilatation, Pathologic , Gelatinases/metabolism , Heart Ventricles/drug effects , Heart Ventricles/pathology , Heart Ventricles/physiopathology , Inflammation Mediators/metabolism , Mice, Inbred C57BL , Mitochondrial Proteins/metabolism , Models, Biological , Vascular Fistula/pathology , Vascular Fistula/physiopathology
3.
Am J Physiol Lung Cell Mol Physiol ; 316(1): L255-L268, 2019 01 01.
Article in English | MEDLINE | ID: mdl-30382767

ABSTRACT

Irrespective of its diverse etiologies, acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) leads to increased permeability of the alveolar-capillary barrier, which in turn promotes edema formation and respiratory failure. We investigated the mechanism of ALI/ARDS lung hyperpermeability triggered by pulmonary exposure of mice to the highly toxic plant-derived toxin ricin. One prominent hallmark of ricin-mediated pulmonary intoxication is the rapid and massive influx of neutrophils to the lungs, where they contribute to the developing inflammation yet may also cause tissue damage, thereby promoting ricin-mediated morbidity. Here we show that pulmonary exposure of mice to ricin results in the rapid diminution of the junction proteins VE-cadherin, claudin 5, and connexin 43, belonging, respectively, to the adherens, tight, and gap junction protein families. Depletion of neutrophils in ricin-intoxicated mice attenuated the damage caused to these junction proteins, alleviated pulmonary edema, and significantly postponed the time to death of the intoxicated mice. Inhibition of matrix metalloproteinase (MMP) activity recapitulated the response to neutrophil depletion observed in ricin-intoxicated mice and was associated with decreased insult to the junction proteins and alveolar-capillary barrier. However, neutrophil-mediated MMP activity was not the sole mechanism responsible for pulmonary hyperpermeability, as exemplified by the ricin-mediated disruption of claudin 18, via a neutrophil-independent mechanism involving tyrosine phosphorylation. This in-depth study of the early stage mechanisms governing pulmonary tissue integrity during ALI/ARDS is expected to facilitate the tailoring of novel therapeutic approaches for the treatment of these diseases.


Subject(s)
Antigens, CD/metabolism , Blood-Air Barrier/metabolism , Cadherins/metabolism , Claudin-5/metabolism , Connexin 43/metabolism , Intercellular Junctions/metabolism , Respiratory Distress Syndrome/metabolism , Ricin/toxicity , Animals , Blood-Air Barrier/pathology , Claudins/metabolism , Collagenases/metabolism , Disease Models, Animal , Humans , Inflammation , Intercellular Junctions/pathology , Mice , Respiratory Distress Syndrome/chemically induced , Respiratory Distress Syndrome/pathology
4.
Sci Rep ; 4: 5987, 2014 Aug 07.
Article in English | MEDLINE | ID: mdl-25100357

ABSTRACT

A complete fingerprint of a tissue sample requires a detailed description of its cellular and extracellular components while minimizing artifacts. We introduce the application of a novel scanning electron microscope (airSEM™) in conjunction with light microscopy for functional analysis of tissue preparations at nanometric resolution (<10 nm) and under ambient conditions. Our metal-staining protocols enable easy and detailed visualization of tissues and their extracellular scaffolds. A multimodality imaging setup, featuring airSEM™ and a light microscope on the same platform, provides a convenient and easy-to-use system for obtaining structural and functional correlative data. The airSEM™ imaging station complements other existing imaging solutions and shows great potential for studies of complex biological systems.


Subject(s)
Electron Microscope Tomography/instrumentation , Imaging, Three-Dimensional/instrumentation , Lung/ultrastructure , Microscopy, Electron, Scanning/instrumentation , Animals , Carbocyanines , Collagen Type I/isolation & purification , Collagen Type I/ultrastructure , Coloring Agents , Electron Microscope Tomography/methods , Extracellular Matrix/ultrastructure , Imaging, Three-Dimensional/methods , Mice , Microscopy, Electron, Scanning/methods , Organometallic Compounds , Rats , Ruthenium Red , Staining and Labeling/methods , Tail/chemistry
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