elastin and Hemorrhage

Topics: Anemia; Animals; Aorta; Aortic Diseases; Chick Embryo; Chickens; Collagen; Copper; Deficiency Diseases; Elastin; Female; Hemorrhage; Lysine; Pregnancy; Swine

Exercise-induced pulmonary hemorrhage (EIPH) is a common condition of Thoroughbred racehorses that is usually responsible for reduced performance, while exercise-associated fatal pulmonary hemorrhage (EAFPH) is characterized by severe pulmonary bleeding of unknown pathogenesis resulting in sudden death during strenuous exercise. The aim of the study was to characterize and compare anamnestic data together with pulmonary gross, histologic, and ultrastructural findings in racehorses with EIPH (n = 10), EAFPH (n = 10), and control horses (n = 5). No differences in anamnesis were identified between the 3 groups. Grossly cranial lobe reddening and edema scores were significantly more prevalent and severe in the EAFPH group compared with the EIPH and control groups. Histologically, hemorrhage scores were higher in the EAFPH group, while hemosiderophages, iron encrustations of collagen and elastin fibers, and vascular remodeling scores were significantly higher in EIPH group compared with the EAFPH and control groups. In all groups, caudal lung locations exhibited a significantly higher score for vascular remodeling, hemosiderophage accumulation, iron encrustation, and type II pneumocyte hyperplasia when compared with cranial, dorsal, and ventral locations. Ultrastructural analysis of perivascular collagen showed fibrils with significantly larger diameters in the EAFPH group compared with the EIPH group but not compared with the control group. This study demonstrates that lungs of horses that experienced EAFPH show significantly less vascular remodeling and other long-term pulmonary abnormalities that characterize horses with EIPH.

Topics: Animals; Collagen; Elastin; Hemorrhage; Horse Diseases; Horses; Iron; Lung; Lung Diseases; Physical Conditioning, Animal; Vascular Remodeling

There is a need for animal models of plaque rupture. We previously reported that elastin fragmentation, due to a mutation (C1039G(+/-)) in the fibrillin-1 (Fbn1) gene, promotes atherogenesis and a highly unstable plaque phenotype in apolipoprotein E deficient (ApoE(-/-)) mice on a Western-type diet (WD). Here, we investigated whether plaque rupture occurred in ApoE(-/-)Fbn1(C1039G+/-) mice and was associated with myocardial infarction, stroke, and sudden death.. Female ApoE(-/-)Fbn1(C1039G+/-) and ApoE(-/-) mice were fed a WD for up to 35 weeks. Compared to ApoE(-/-) mice, plaques of ApoE(-/-)Fbn1(C1039G+/-) mice showed a threefold increase in necrotic core size, augmented T-cell infiltration, a decreased collagen I content (70 ± 10%), extensive neovascularization, intraplaque haemorrhage, and a significant increase in matrix metalloproteinase-2, -9, -12, and -13 expression or activity. Plaque rupture was observed in 70% of ascending aortas and in 50% of brachiocephalic arteries of ApoE(-/-)Fbn1(C1039G+/-) mice. In ApoE(-/-) mice, plaque rupture was not seen in ascending aortas and only in 10% of brachiocephalic arteries. Seventy percent of ApoE(-/-)Fbn1(C1039G+/-) mice died suddenly, whereas all ApoE(-/-) mice survived. ApoE(-/-)Fbn1(C1039G+/-) mice showed coronary plaques and myocardial infarction (75% of mice). Furthermore, they displayed head tilt, disorientation, and motor disturbances (66% of cases), disturbed cerebral blood flow (73% of cases; MR angiograms) and brain hypoxia (64% of cases), indicative of stroke.. Elastin fragmentation plays a key role in plaque destabilization and rupture. ApoE(-/-)Fbn1(C1039G+/-) mice represent a unique model of acute plaque rupture with human-like complications.

Topics: Animals; Aorta; Apolipoproteins E; Biomarkers; Brachiocephalic Trunk; Cardiomegaly; Carotid Artery, Common; Cerebrovascular Circulation; Death, Sudden; Diet, Western; Disease Models, Animal; Elastin; Female; Fibrillin-1; Fibrillins; Hemorrhage; Hypoxia, Brain; Mice; Microfilament Proteins; Microvessels; Myocardial Infarction; Neovascularization, Pathologic; Nervous System Diseases; Plaque, Atherosclerotic; Rupture, Spontaneous; Stroke; Ventricular Dysfunction, Left

Human leukocyte elastase (HLE) is a proteinase capable of degrading a variety of proteins. Under normal circumstances, the proteolytic activity of HLE is effectively controlled by its natural inhibitors. However, an imbalance between elastase and its endogenous inhibitors may result in several pathophysiological states such as chronic obstructive pulmonary disease, asthma, emphysema, cystic fibrosis, and chronic inflammatory diseases. It is anticipated that an orally active HLE inhibitor could be useful for the treatment of these diseases. 2-(9-(2-Piperidinoethoxy)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yloxymethyl)-4-(1-methylethyl)-6-methoxy-1,2-benzisothiazol-3(2H)-one-1,1-dioxide (SSR69071) is a potent inhibitor of HLE, with the inhibition constant (K(i)) and the constant for inactivation process (k(on)) being 0.0168 +/- 0.0014 nM and 0.183 +/- 0.013 10(6)/mol sr, respectively. The dissociation rate constant, k(off), was 3.11 + 0.37 10(-6)/s. SSR69071 displays a higher affinity for human elastase than for rat (K(i) = 3 nM), mouse (K(i) = 1.8 nM), and rabbit (K(i) = 58 nM) elastases. Bronchoalveolar lavage fluid from mice orally treated with SSR69071 inhibits HLE (ex vivo), and in this model, SSR69071 has a dose-dependent efficacy with an ED(50) = 10.5 mg/kg p.o. SSR69071 decreases significantly the acute lung hemorrhage induced by HLE (ED(50) = 2.8 mg/kg p.o.) in mice. Furthermore, SSR69071 prevents carrageenan- (ED(30) = 2.2 mg/kg) and HLE-induced (ED(30) = 2.7 mg/kg) paw edema in rats after p.o. administration. In conclusion, SSR69071 is a selective, orally active, and potent inhibitor of HLE with good penetration in respiratory tissues.

Topics: Algorithms; Animals; Bronchoalveolar Lavage Fluid; Carrageenan; Cyclic S-Oxides; Dose-Response Relationship, Drug; Edema; Elastin; Enzyme Inhibitors; Hemorrhage; Humans; Hydrolysis; Kinetics; Leukocyte Elastase; Male; Mice; Oligopeptides; Rabbits; Rats; Thiazoles

Structure and content of atherosclerotic plaque varies between patients and may be indicative of their risk for embolisation. This study aimed to construct parametric images of B-scan texture and assess their potential for predicting plaque morphology. Sequential transverse in vitro scans of 10 carotid plaques, excised during endarterectomy, were compared with macrohistology maps of plaque content. Multidiscriminant analysis combined the output of 157 statistical and textural algorithms into five separate texture classes, displayed as ultrasound (US) texture classification images (UTCI). Visual comparison between corresponding UTCI and histology maps found the five texture classes matched with the location of fibrin, elastin, calcium, haemorrhage or lipid. However, histology preparation removes calcium and lipid and, so, can affect the structural integrity of atherosclerotic plaques. Soft tissue regions smaller than the UTCI kernel, (0.87 mm x 0.85 mm x 3.9 mm), such as blood clots, are also difficult to detect by UTCI. These factors demonstrate limitations in the use of histology as a "gold standard" for US tissue characterisation.

Topics: Arteriosclerosis; Calcium; Carotid Arteries; Carotid Stenosis; Elastin; Endarterectomy, Carotid; Fibrin; Hemorrhage; Humans; Image Processing, Computer-Assisted; In Vitro Techniques; Lipids; Ultrasonography

A neutrophil elastase inhibitor FR901277 was examined for its inhibitory effect on degradation of natural substrate elastin in vitro, and on acute inflammatory states and pulmonary emphysema in vivo.. Elastin-congo red was used as a substrate for elastin degradation assay. Paw edema in male C57BL mice (6 weeks old) and pulmonary hemorrhage in female golden hamsters (5 weeks old) were induced by topical injection of human neutrophil elastase (HNE). Pulmonary emphysema in male golden Syrian hamsters (10 weeks old) was provoked by intratracheal instillation of porcine pancreatic elastase. In all in vivo experiments. FR901277 was administered prior to elastase treatment.. Elastin degradation by HNE was monitored spectrophotometrically with elastin-congo red. Foot swelling was measured by calipers. Pulmonary hemorrhage was assessed by hemoglobin concentration in bronchoalveolar lavage fluid. As emphysematous parameters, quasi-static lung compliance and vital capacity were measured.. FR901277 inhibited HNE-induced elastin degradation. Systemic treatment with FR901277 significantly inhibited paw edema and pulmonary hemorrhage. Intratracheal treatment with FR901277 significantly ameliorated changes in pulmonary function.. These results suggest that FR901277 inhibits the elastase activity potently both in vitro and in vivo, and that elastase may play a role at least in part in pathogenesis of pulmonary emphysema.

Topics: Amides; Animals; Cricetinae; Edema; Elastin; Enzyme Inhibitors; Female; Hemorrhage; Humans; Inflammation; Leukocyte Elastase; Lung Diseases; Male; Mesocricetus; Mice; Mice, Inbred C57BL; Pancreatic Elastase; Pulmonary Emphysema; Swine

The thrombospondins are a family of extracellular calcium-binding proteins that modulate cellular phenotype. Thrombospondin-1 (TSP-1) reportedly regulates cellular attachment, proliferation, migration, and differentiation in vitro. To explore its function in vivo, we have disrupted the TSP-1 gene by homologous recombination in the mouse genome. Platelets from these mice are completely deficient in TSP-1 protein; however, thrombin-induced platelet aggregation is not diminished. TSP-1-deficient mice display a mild and variable lordotic curvature of the spine that is apparent from birth. These mice also display an increase in the number of circulating white blood cells, with monocytes and eosinophils having the largest percent increases. The brain, heart, kidney, spleen, stomach, intestines, aorta, and liver of TSP-1-deficient mice showed no major abnormalities. However, consistent with high levels of expression of TSP-1 in lung, we observe abnormalities in the lungs of mice that lack the protein. Although normal at birth, histopathological analysis of lungs from 4-wk-old TSP-1-deficient mice reveals extensive acute and organizing pneumonia, with neutrophils and macrophages. The macrophages stain for hemosiderin, indicating that diffuse alveolar hemorrhage is occurring. At later times, the number of neutrophils decreases and a striking increase in the number of hemosiderin-containing macrophages is observed associated with multiple-lineage epithelial hyperplasia and the deposition of collagen and elastin. A thickening and ruffling of the epithelium of the airways results from increasing cell proliferation in TSP-1-deficient mice. These results indicate that TSP-1 is involved in normal lung homeostasis.

Topics: Animals; Blood Platelets; Cells, Cultured; Collagen; Congenital Abnormalities; DNA; Elastin; Eosinophils; Epithelial Cells; Genetic Vectors; Hemorrhage; Hemosiderin; Homeostasis; Hyperplasia; Leukocyte Count; Lordosis; Lung; Macrophages; Mice; Mice, Knockout; Monocytes; Neutrophils; Platelet Aggregation; Pneumonia; Proteins; Radiography; Recombination, Genetic; Restriction Mapping; Ribonucleases; Thrombin; Thrombospondin 1; Transfection

Inhibitors of human leukocyte elastase (HLE) may exert potent therapeutic effects on pulmonary emphysema, adult respiratory distress syndrome and other diseases involving tissue degradation. 7-(4-Chlorophenylsulfonyl-L-glutanyl)amino-5-methyl-2-isopro pylamino-4H-3,1- benzoxazin-4-one (TEI-5624) and 7-(4-chlorophenylsulfonyl-L-lysyl)amino-5-methyl-2- isopropylamino-4H-3,1-benzoxazin-4-one (TEI-6344), two derivatives of 5-methyl-4H-3,1-benzoxazin-4-one, showed strong and highly specific inhibition of human sputum elastase (HSE), which is equivalent to HLE, with Ki values of 6.91 and 16.3 nM, respectively. The selectivity of TEI-5624 for HSE vs. several proteinases ranged from 300-fold to 45,000-fold in favor of HSE. TEI-5624 and TEI-6344 also efficiently prevented degradation of insoluble elastin by stimulated polymorphonuclear leukocytes. The elastase inhibitory capacity of these compounds was not affected by treatment with stimulated polymorphonuclear leukocytes or Pseudomonas aeruginosa-origin elastase. When administered intratracheally to hamsters. TEI-5624 and TEI-6344 were eliminated from the lung with half-times of 85 and 240 min, respectively. In acute injury induced by intratracheal administration of HSE in hamsters, these compounds significantly suppressed pulmonary hemorrhage when administered intratracheally (1 mg/kg) either 30 or 240 min before challenge with HSE (1 mg/kg). HSE-induced emphysema in hamsters was also prevented by TEI-5624 (1 mg/kg) administered intratracheally 7 hr after HSE administration (1 mg/kg). These results suggest that TEI-5624 and TEI-6344 may be useful therapeutic agents for the treatment of HLE-mediated diseases.

Topics: Amino Acid Sequence; Animals; Benzoxazines; Binding Sites; Cells, Cultured; Cricetinae; Drug Stability; Elastin; Hemorrhage; Humans; Leukocyte Elastase; Lung Diseases; Male; Mesocricetus; Molecular Sequence Data; Oxazines; Oxidation-Reduction; Pancreatic Elastase; Sputum; Sulfonamides

Topics: Animals; Collagen; Disease Models, Animal; Elastin; Hemorrhage; Inflammation; Intubation, Intratracheal; Lung; Lung Diseases; Papain; Pulmonary Edema; Pulmonary Emphysema; Rabbits

Amino acid analysis of human fetal lung elastin was undertaken in 49 instances of live-born neonates, ranging from 380 g to full term, and in 3 abortuses of 12-14 wk gestation. The data suggest that formation of the cross-linking agents, desmosine and isodesmosine, occurs early, between 14 and 22 wk. The ratio of neutral to charged amino acids remains low until the 36th wk when it attains adult levels. The composition of elastin was independent of sex and duration of survival. In three neonatal pulmonary diseases (respiratory distress syndrome, atelectasis, and hemorrhage) ratios were significantly lower than those found in nondiseased lungs. This may be a reflection of immaturity or may be a predisposing factor in neonatal lung disease. The latter hypothesis is attractive and receives indirect support from the association of a more polar elastin with other diseases, including adult emphysema and atheromatous aortic change.Our finding of relatively high polarity in elastin from human fetal lung is consistent with previous observations in a variety of fetal organs of other species.

Topics: Age Factors; Amino Acids; Birth Weight; Chemical Phenomena; Chemistry; Elastin; Gestational Age; Hemorrhage; Humans; Infant, Newborn; Infant, Newborn, Diseases; Lung; Pulmonary Atelectasis; Respiratory Distress Syndrome, Newborn; Sex Factors

Topics: Aminopropionitrile; Animals; Aorta, Abdominal; Arteries; Body Weight; Collagen; Disease Models, Animal; Edema; Elastin; Female; Ferrocyanides; Haplorhini; Hemorrhage; Hemosiderosis; Iliac Artery; Lathyrism; Macaca; Male; Sternum; Thoracic Arteries

Topics: Animals; Arteritis; Basement Membrane; Chromatography, DEAE-Cellulose; Chromatography, Ion Exchange; Dogs; Edetic Acid; Elastin; Electrophoresis; Hemorrhage; Humans; Hydrogen-Ion Concentration; In Vitro Techniques; Inflammation; Leukocytes; Lysosomes; Microbial Collagenase; Pancreatic Elastase; Peptide Hydrolases; Rabbits

Topics: Acute Disease; Animals; Ascitic Fluid; Dogs; Elastic Tissue; Elastin; Enzyme Precursors; Fasting; Female; Hemorrhage; In Vitro Techniques; Male; Pancreatic Elastase; Pancreatic Extracts; Pancreatitis; Thrombosis; Time Factors; Trypsin