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Necrotizing alveolar capillaritis in autopsy cases of microscopic polyangiitis. Incidence, histopathogenesis, and relationship with systemic vasculitis.

OBJECTIVES: To determine the incidence of necrotizing alveolar capillaritis, to elucidate its histopathogenesis and the most reliable histopathologic features for its detection, and to explore its relationship with systemic vasculitis in microscopic polyangiitis. METHODS: Twenty-five autopsy cases of microscopic polyangiitis were examined. Double staining with periodic acid-silver methenamine and trichrome was used. RESULTS: Periodic acid-silver methenamine and trichrome staining proved to be a useful and convenient method for the detection of necrotizing alveolar capillaritis. Capillaritis was detected in 10 (40%) of the 25 cases studied. Of 18 cases that exhibited the early degenerative stage of systemic vasculitis, capillaritis was seen in 10 (56%). Fibrinoid necrosis of the alveolar wall was the most reliable histopathologic feature for detecting necrotizing alveolar capillaritis in microscopic polyangiitis. The early stage of capillaritis displayed very little neutrophil exudation, and conspicuous accumulation of neutrophils developed after fibrinoid necrosis. Statistical analysis revealed that alveolar capillaritis had a statistically significant correlation (P < .05) with necrotizing vasculitis of the pulmonary circulatory system. Capillaritis tended to occur when systemic vasculitis of microscopic polyangiitis was in its early degenerative stage. CONCLUSION: Necrotizing alveolar capillaritis was detected in about half of the microscopic polyangiitis autopsy cases that exhibited the early degenerative stage of systemic vasculitis, and results based on earlier reports of clinical observations may have been too conservative.

Adult↗

Antiphospholipid antibodies as a cause of pulmonary capillaritis and diffuse alveolar hemorrhage: a case series and literature review.

OBJECTIVES: To discuss the clinical manifestations and possible pathogenic mechanisms of the unusual syndrome of diffuse alveolar hemorrhage (DAH) and pulmonary capillaritis without thrombosis in the setting of the primary antiphospholipid antibody syndrome (PAPS). METHODS: Four men with DAH and capillaritis in the setting of PAPS are identified. Their clinical presentations, laboratory, radiographic, and pathologic findings are reviewed as is their clinical course and response to therapy. In addition, the literature regarding DAH and pulmonary capillaritis in the setting of PAPS is reviewed. RESULTS: The patients presented with dyspnea, hemoptysis, fever, hypoxia, and diffuse alveolar infiltrates; none had evidence of acute thromboembolic disease. All secondary causes of DAH were ruled out. All patients had positive testing for the lupus anticoagulant and high-titer anticardiolipin antibodies, including antibodies against the beta-2-glycoprotein I antigen. Three cases had lung biopsies that revealed pulmonary capillaritis and DAH with no evidence of thrombosis. All patients improved with high-dose corticosteroids. Recurrent disease in the setting of aggressive immunosuppression responded to intravenous immunoglobulin. Antiphospholipid antibody-mediated endothelial cell activation in the absence of thrombosis may induce capillaritis as seen in these cases. CONCLUSIONS: The syndrome of DAH and pulmonary capillaritis is further defined. Evidence supports a causative relationship between PAPS, pulmonary capillaritis, and DAH in the absence of thromboembolic disease. Further elucidation of a possible nonthrombotic mechanism of antiphospholipid antibody-mediated pathology is needed to guide future therapies for this unusual manifestation of PAPS.

Adult↗

Neoangiogenesis and sinusoidal "capillarization" in dysplastic nodules of the liver.

The blood supply of hepatocellular carcinoma (HCC) is primarily arterial. Recent studies reported differences of vascular, especially arterial, supply among low- and high-grade dysplastic nodules and HCC. We assessed arterialization using monoclonal antibody specific for smooth muscle actin as well as simultaneous changes in sinusoidal capillarization in cirrhotic nodules, dysplastic nodules, and HCC. We immunohistochemically stained 56 cirrhotic nodules, 20 low-grade dysplastic nodules, 27 high-grade dysplastic nodules, and 20 HCCs for alpha smooth muscle actin (to identify unpaired arteries (i.e., arteries not accompanied by bile ducts) and CD34 (indicating sinusoidal capillarization). Distribution and number of unpaired arteries and distribution of sinusoidal capillarization were graded semiquantitatively. Unpaired arteries were rare in cirrhotic nodules, significantly more common in dysplastic nodules of both types (p < 0.00001), and most common in HCC. Sinusoidal capillarization was least common in cirrhotic nodules, significantly more common in dysplastic nodules (p < 0.0035), and most common in HCC. No topographic relationship between unpaired arteries and sinusoidal capillarization was identified. These findings showed that (1) distributions of sinusoidal capillarization and unpaired arteries in dysplastic nodules are intermediate between those in cirrhotic nodules and HCC, supporting dysplastic nodules as premalignant lesions; (2) unpaired arteries are histologically useful for distinguishing dysplastic nodules from large cirrhotic nodules; and (3) areas of sinusoidal capillarization within dysplastic nodules are unrelated to location of arterialization.

Actins↗

Diffuse alveolar hemorrhage with underlying isolated, pauciimmune pulmonary capillaritis.

Diffuse alveolar hemorrhage (DAH) resulting from pulmonary capillaritis typically accompanies the systemic vasculitides and collagen vascular diseases. Isolated pulmonary capillaritis and DAH without systemic disease occurs in patients with antineutrophil cytoplasmic antibodies. However, isolated pulmonary capillaritis and DAH is not described for patients without clinical or serologic evidence for an underlying systemic disease. To describe such patients, we undertook a retrospective chart review of 29 patients with DAH and biopsy-proven pulmonary capillaritis from seven Denver hospitals. Eight (28%) were diagnosed with isolated pulmonary capillaritis without clinical, serologic, or histologic evidence of an associated illness. Their median age was 30 yr. No association with occupational or drug exposures was identified. All had lower respiratory tract symptoms; seven had upper respiratory tract symptoms. None demonstrated systemic disease or evidence of glomerulonephritis. All were antineutrophil cytoplasmic antibody negative. Other serologies were not significant where measured. Direct immunofluorescence studies of lung tissue were negative in five. Six presented with acute respiratory failure, four requiring mechanical ventilation. One died during initial hospitalization; seven survived. Median follow-up is 43 mo (7 to 73 mo). Five remain in remission. Two experienced multiple recurrences of DAH but without development of systemic disease while on therapy. Herein we characterize DAH and isolated pulmonary capillaritis in the absence of clinical, serologic, or histologic evidence indicating an accompanying systemic illness. The prognosis for this group appears favorable.

Adult↗

Pulmonary capillaritis and alveolar hemorrhage. Update on diagnosis and management.

Pulmonary vascular inflammatory disorders may involve all components of the pulmonary vasculature, including capillaries. The principal histopathologic features of pulmonary capillaritis include capillary wall necrosis with infiltration by neutrophils, interstitial erythrocytes, and/or hemosiderin, and interalveolar septal capillary occlusion by fibrin thrombi. Immune complex deposition is variably present. Patients often present clinically with diffuse alveolar hemorrhage, which is characterized by dyspnea and hemoptysis; diffuse, bilateral, alveolar infiltrates on chest radiograph; and anemia. Pulmonary capillaritis has been reported with variable frequency and severity as a manifestation of Wegener's granulomatosis, microscopic polyarteritis, systemic lupus erythematosus, Goodpasture's syndrome, idiopathic pulmonary renal syndrome, Behçet's syndrome, Henoch-Schönlein purpura, IgA nephropathy, antiphospholipid syndrome, progressive systemic sclerosis, and diphenylhydantoin use. In addition to history, physical examination, and routine laboratory studies, certain ancillary laboratory tests, such as antineutrophil cytoplasmic antibodies, antinuclear antibodies, and antiglomerular basement membrane antibodies, may help diagnose an underlying disease. Diagnosis of pulmonary capillaritis can be made by fiberoptic bronchoscopy with transbronchial biopsy, but thoracoscopic biopsy is often employed. Since many disorders can result in pulmonary capillaritis with diffuse alveolar hemorrhage, it is crucial for clinicians and pathologists to work together when attempting to identify an underlying disease. Therapy depends on the disorder that gave rise to the pulmonary capillaritis and usually includes corticosteroids and cyclophosphamide or azathioprine. Since most diseases that result in pulmonary capillaritis are treated with immunosuppression, infection must be excluded aggressively.

Anemia↗

Isolated pulmonary capillaritis and diffuse alveolar hemorrhage in rheumatoid arthritis and mixed connective tissue disease.

STUDY OBJECTIVES: To demonstrate that pulmonary capillaritis and diffuse alveolar hemorrhage (DAH) occur and are isolated to the lung and therefore not part of systemic vasculitis at the time of the DAH episode in rheumatoid arthritis (RA) and mixed connective tissue disease (MCTD). DESIGN: Lung biopsy specimens from patients with DAH were reviewed and those with the histologic features of pulmonary capillaritis were identified. SETTING: The patients were selected from seven Denver-area general hospitals. PATIENTS: Fifty-eight patients with biopsy specimen proved pulmonary capillaritis (1991 to 1997) were identified and classified according to disease. Three patients met the American Rheumatism Association criteria for RA and one patient fulfilled clinical and serologic criteria for MCTD. INTERVENTIONS: All clinical, laboratory, and radiographic data on initial presentation and at follow-up periods were extracted from the charts of the four study patients. Histologic slides were reviewed and immunofluorescent studies of lung tissue were performed. MEASUREMENTS AND RESULTS: All four patients had a connective tissue disease diagnosis prior to the DAH episode. Symptoms referable to pulmonary capillaritis were of short duration (2 to 14 days) and there was no clinical or serologic evidence for an accompanying systemic vasculitis, in particular glomeronephritis. Three patients, two with RA and one with MCTD, demonstrated pulmonary immune complex deposition. Three resolved their illness following IV methylprednisilone and cyclophosphamide therapy. One RA patient died following a myocardial infarction. In the three survivors, no further episodes of DAH have occurred after a mean of 24 months (range, 10 to 48 months). CONCLUSIONS: To our knowledge, these are the first cases of DAH due to pulmonary capillaritis documented to complicate RA and MCTD. The capillaritis was not part of a systemic vasculitis at the time of the DAH episode, but rather represented an isolated small-vessel vasculitis of the lungs in this group of patients. Immune complex deposition may be involved in the pathogenesis.

Adult↗

[The coordinated expression of laminin and its integrin receptor in hepatic sinusoidal capillarization].

OBJECTIVE: To explore the expression of laminin and its integrin receptor alpha 6 in sinusoidal capillaration. METHODS: The rat hepatic fibrosis model was established by injection carbon tetrachloride subcutaneously. Liver sections were examined by scanning electron microscopy and special staining. Then expressions of laminin and integrin alpha 6 subunit were observed by immunohistochemistry and dot immuno-blotting. RESULTS: The pathologic character of hepatic fibrosis-sinusoidal capillaration was observed. Sinusoidal capillaration is characterized by defenestration of sinusoidal endothelial cells (SEC) and basement membrane forming and phenotype transformation. By immunohistochemistry staining. The deposition of laminin surrounding sinusoids according to fibrosis stage was 0, 1.92%, 6.02%, 9.68%, 14.14% respectively, statistically different from each other (P < 0.05). In normal rat no expression of integrin alpha 6 were observed in SEC membranes. When capillaration integrin alpha 6 was detected in a continuous pattern along the sinusoidal in accordance with laminin assembly. The content of integrin alpha 6 in fibrotic liver tissues were significantly higher than in normal liver tissues as measured by dot immuno-blotting (P < 0.05). CONCLUSIONS: During fibrogenesis laminin continuously accumulate in liver tissues and form basement membrane resulting in sinusoidal capillaration, meanwhile are company with induced expression of LN-binding-integrin alpha 6 on SEC membranes. These results suggest that coordinated expression of laminin and laminin-binding-integrin might be important in pathogenesis of sinusoidal capillaration and hepatic fibrosis.

Animals↗

Increased capillarity in skeletal muscle of growing guinea pigs acclimated to cold and hypoxia.

Capillarity was evaluated on transverse sections of frozen gastrocnemius and soleus muscles of young, growing guinea pigs exposed to the combined stresses of cold (6 degrees C) (C) and hypoxia (ambient PO2 = 85 Torr) (H) for up to 16 weeks and these data were compared to those obtained in a control group of guinea pigs kept in Denver (22 degrees C, ambient PO2 = 133 Torr). Capillarity was assessed from measurements of capillary density and capillarity density to fiber density ratios. Mean (R) and maximal (R95) diffusion distances were measured by the closest individual method. The body growth rate of guinea pigs exposed to C + H was the same as that in the control condition. The gastrocnemius muscle grew at the same rate as in the control guinea pigs. Exposure to C + H produced a significant (P less than 0.001) increase in the capillary density and the C/F of the gastrocnemius, reducing the mean and the maximal diffusion distances. However, the soleus muscles of the guinea pigs in C + H did not grow at the same rate and relative to body size the soleus muscles of these guinea pigs in C + H were smaller due to their smaller fiber cross-section area; consequently, there was a relatively larger capillarity in these muscles. It is hypothesized that the increased muscle capillarity in animals exposed to C + H results from a marked lowering of the tissue PO2 which may result from a leftward shift of the Hb-O2 dissociation curve.

Acclimatization↗

Pulmonary capillaritis in lung transplant recipients: treatment and effect on allograft function.

The clinical outcomes of lung transplant recipients presenting with post-transplant pulmonary capillaritis have not been well described. We retrospectively reviewed 40 cases of biopsy-proven pulmonary capillaritis in lung transplant recipients. Patients presented with a clinical syndrome characterized by dyspnea, hypoxemia, abnormal chest X-ray, and a decrease in forced expiratory volume in 1 second (FEV1); 25% presented with hemoptysis, and 18% with fulminant respiratory failure. Therapy with intravenous corticosteroids resulted in clinical improvement in 17 cases (43%). A response to plasmapheresis was seen in 12 (67%) of 18 cases refractory to corticosteroids. There were 5 deaths within 3 months of diagnosis. Nine (82%) of 11 lung transplant recipients who presented with capillaritis within 4 weeks post-transplant were alive at 1 year; all but 1 patient achieved expected percent predicted FEV1 values. Only 3 (14%) of 21 who presented with capillaritis > 1 month after transplant had a >20% decrease in the FEV1 after 12 months. These results suggest that post-transplant pulmonary capillaritis is (1) likely a form of acute allograft rejection clinically and histologically distinct from typical acute rejection, (2) less responsive to corticosteroid therapy than typical acute rejection, and (3) not associated with long-term adverse effects on allograft function.

Capillaries↗

Studies on capillarization of the hepatic sinusoids in alcoholic liver disease.

It has been reported that basement membranes were found around the sinusoidal walls in cirrhotic livers, indicating the development of capillarization of the sinusoids. It has been also emphasized that capillarization of the sinusoids is more prominent in alcoholic liver disease (ALD). In the present study, factor VIII related antigen (VIII-Ag) and UEA-1 were identified immunohistochemically in order to analyze capillarization of the sinusoids in chronic liver diseases. Electron microscopic studies on the endothelial cells and sinusoids were also performed. Electron microscopic studies revealed that the number of fenestra in the endothelial cells decreased and basement membranes were clearly observed in the space of Disse from an early stage of ALD. However, these changes were not observed in the early stage of non-ALD. VIII-Ag or UEA-1 was not stainable in the sinusoidal cells of normal livers or at an early stage of non-ALD. However, in ALD, both VIII-Ag and UEA-1 were clearly demonstrated in the sinusoidal cells from the early stage of fibrosis. These results suggest that the sinusoidal endothelial cells may transform to vascular endothelial cells from an early stage of ALD. The alterations in the sinusoidal endothelium and the basement membrane formation in the Disse space indicate that capillarization of the sinusoid may occur. Capillarization of the sinusoid may cause a disturbance in exchanges of many bioactive substances between the sinusoidal blood and hepatocytes across the Disse space and may thereby contribute to the pathogenesis of ALD.

Basement Membrane↗

Pulmonary capillaritis.

Vasculitis, inflammation, and necrosis of blood vessels can involve any size or type of vessel in the pulmonary vasculature, including the capillaries, so-called capillaritis. Although pulmonary capillaritis is a histopathologic diagnosis that is not pathognomonic of a specific disorder, it usually signals the presence of an underlying systemic vasculitis or collagen vascular disease. Patients with pulmonary capillaritis usually present with bilateral infiltrates on chest radiographs and can be acutely ill with diffuse alveolar hemorrhage that may be life threatening. Therapy depends on diagnosis of the underlying disease that gave rise to the capillaritis. Since many of the disorders leading to capillaritis are treated by immunosuppression with corticosteroids and cyclophosphamide or azathioprine, infection must be excluded early in the course of therapy.

Capillaries↗

The influence of endurance and resistance exercise on muscle capillarization in the elderly: a review.

AIM: Ageing is one of many factors altering skeletal muscle. Conflicting results from previous studies guided this review to identify what has been found to date regarding microvascular adaptations in skeletal muscle as the result of ageing or inactivity, and endurance or resistance training interventions. Additionally, this review attempts to identify the variety of parameters for determining capillarization and discuss why these might be contributing to the conflicting results. METHODS: Electronic database searches were conducted for full-length articles using relevant keywords related to ageing, muscle capillarization and exercise in all fields. Cross-sectional, longitudinal, training and review papers were included. Several studies on younger subject adaptation were also included for comparison. RESULTS: Ageing and inactivity both result in regressive structural and functional changes to skeletal muscle capillarization. The rate and magnitude of decline is still unknown. Endurance training can positively effect structural changes to capillarity. There is conflicting evidence regarding the effects of resistance training. Training intensity may be an important factor. Biopsy sampling, histological staining and several measurement protocols may be providing inaccurate estimations of capillarity. CONCLUSION: Part of the difficulty in determining the nature of these relationships has been the inconsistency in research conducted regarding age groups and controlling for past and present activity patterns. Further difficulties comparing across studies arise due to the variety of methods and parameters used to sample and analyse muscle tissue. Standardizing methodology will allow future research to yield more consistent results.

Adult↗

The effect of hyperthyroidism on capillarity and oxidative capacity in rat soleus and gastrocnemius muscles.

Muscle fibre composition and capillarity were evaluated in frozen sections stained for myosin ATPase of the soleus and the white area of the medial head of the gastrocnemius of rats made hyperthyroid by injections of triiodothyronine (300-400 micrograms/kg body weight, every other day) for 2, 3 and 4 weeks. O2 consumption of homogenates of these muscles in the presence of excess inorganic phosphate (Pi) and ADP with pyruvate and malate as substrates was also measured. Increased oxidative capacity was observed in the soleus homogenates of hyperthyroid animals after 2 weeks of treatment while no changes were observed in the oxidative capacity of the homogenates of the white area of the medial head of the gastrocnemius, even after 4 weeks of treatment. Hyperthyroid animals showed a greater capillarity than controls in both muscles. In the soleus this was evident after 2 weeks of treatment while in the white area of the medial head of the gastrocnemius, it was evident only after 4 weeks of treatment. Fibre composition was affected in the soleus after 4 weeks of treatment. In control animals two fibre types were present in the soleus: slow-twitch oxidative fibres (s.o. or type I fibres) with a high ATPase activity after acid pre-incubation and fast-twitch glycolytic oxidative fibres (f.o.g. or type IIa fibres) with a low ATPase activity after acid pre-incubation. In the soleus of the hyperthyroid animals, a third fibre type with intermediate ATPase activity after acid pre-incubation was also present. This most probably represents a change in the type of myosin being synthesized by some fibres. No changes in fibre composition were observed in the white area of medial head of the gastrocnemius which was made up of only fast-twitch glycolytic fibres (f.g. or type IIb fibres). The changes in oxidative capacity and capillarity in the soleus preceded and did not seem to be related to the changes in the type of myosin being synthesized. The increased capillarity found in the white area of the medial head of the gastrocnemius of the hyperthyroid animals, in the absence of an increase in the oxidative capacity, indicates that the latter is not the only factor that determines capillarity in skeletal muscle.

Adenosine Triphosphatases↗

Neoangiogenesis and sinusoidal capillarization in hepatocellular carcinoma: correlation between dynamic CT and density of tumor microvessels.

PURPOSE: To retrospectively evaluate the correlation between the degree of contrast enhancement on dynamic computed tomographic (CT) scans and the degree of neoangiogenesis and sinusoidal capillarization in hepatocellular carcinoma (HCC). MATERIALS AND METHODS: The institutional review board did not require approval or informed patient's consent for the review of medical records or images. Dynamic CT scans of 97 nodular HCCs in 97 patients (79 men, 18 women; age range, 29-73 years; mean age, 54 years) were evaluated in terms of the attenuation change in the arterial, portal venous, and delayed phases, and the results were correlated with the number of unpaired arteries and the degree of sinusoidal capillarization at histopathologic examination. The mean attenuation value of the nodular HCCs on triple-phase helical CT scans was correlated with the number of unpaired arteries and the degree of sinusoidal capillarization. Statistical analysis was performed with the Spearman rank correlation test. RESULTS: The number of unpaired arteries in the nodular HCCs was found to correlate with the degree of contrast enhancement in the arterial phase (r = 0.225, P = .027), but did not correlate with the degree of contrast enhancement in the portal and delayed phases. The degree of sinusoidal capillarization did not correlate linearly with the mean attenuation of the nodular HCCs in any phase of contrast enhancement. CONCLUSION: The degree of contrast enhancement of the nodular HCCs in the arterial phase tended to correlate with the number of unpaired arteries, but no correlation was evident between the degree of contrast enhancement and sinusoidal capillarization in any phase of CT imaging.

Adult↗

Muscle capillarization O2 diffusion distance, and VO2 kinetics in old and young individuals.

The relationships between muscle capillarization, estimated O2 diffusion distance from capillary to mitochondria, and O2 uptake (VO2) kinetics were studied in 11 young (mean age, 25.9 yr) and 9 old (mean age, 66.0 yr) adults. VO2 kinetics were determined by calculating the time constants (tau) for the phase 2 VO2 adjustment to and recovery from the average of 12 repeats of a 6-min, moderate-intensity plantar flexion exercise. Muscle capillarization was determined from cross sections of biopsy material taken from lateral gastrocnemius. Young and old groups had similar VO2 kinetics (tau VO2-on = 44 vs. 48 s; tau VO2-off = 33 vs. 44 s, for young and old, respectively), muscle capillarization, and estimated O2 diffusion distances. Muscle capillarization, expressed as capillary density or average number of capillary contacts per fiber/average fiber area, and the estimates of diffusion distance were significantly correlated to VO2-off kinetics in the young (r = -0.68 to -0.83; P < 0.05). We conclude that 1) capillarization and VO2 kinetics during exercise of a muscle group accustomed to everyday activity (e.g., walking) are well maintained in old individuals, and 2) in the young, recovery of VO2 after exercise is faster, with a greater capillary supply over a given muscle fiber area or shorter O2 diffusion distances.

Adult↗

Lower capillarization, VEGF protein, and VEGF mRNA response to acute exercise in the vastus lateralis muscle of aged vs. young women.

In humans, the majority of studies demonstrate an age-associated reduction in the number of capillaries surrounding skeletal muscle fibers; however, recent reports in rats suggest that muscle capillarization is well maintained with advanced age. In sedentary and trained men, aging lowers the number of capillaries surrounding type II, but not type I, skeletal muscle fibers. The fiber type-specific effect of aging on muscle capillarization is unknown in women. Vascular endothelial growth factor (VEGF) is important in the basal maintenance of skeletal muscle capillarization, and lower VEGF expression is associated with increased age in nonskeletal muscle tissue of women. Compared with young women (YW), we hypothesized that aged women (AW) would demonstrate 1) lower muscle capillarization in a fiber type-specific manner and 2) lower VEGF and VEGF receptor expression at rest and in response to acute exercise. Nine sedentary AW (70 + 8 yr) and 11 YW (22 + 3 yr) had vastus lateralis muscle biopsies obtained before and at 4 h after a submaximal exercise bout for the measurement of morphometry and VEGF and VEGF receptor expression. In AW compared with YW, muscle capillary contacts were lower overall (YW: 2.36 + 0.32 capillaries; AW: 2.08 + 0.17 capillaries), specifically in type II (YW: 2.37 + 0.39 capillaries; AW: 1.91 + 0.36 capillaries) but not type I fibers (YW: 2.36 + 0.34 capillaries; AW: 2.26 + 0.24 capillaries). Muscle VEGF protein was 35% lower at rest, and the exercise-induced increase in VEGF mRNA was 50% lower in AW compared with YW. There was no effect of age on VEGF receptor expression. These results provide evidence that, in the vastus lateralis of women, 1) capillarization surrounding type II muscle fibers is lower in AW compared with YW and 2) resting VEGF protein and the VEGF mRNA response to exercise are lower in AW compared with YW.

Adolescent↗

Arsenic stimulates sinusoidal endothelial cell capillarization and vessel remodeling in mouse liver.

UNLABELLED: Trivalent arsenic [As(III)] is a well-known environmental toxicant that causes a wide range of organ-specific diseases and cancers. In the human liver, As(III) promotes vascular remodeling, portal fibrosis, and hypertension, but the pathogenesis of these As(III)-induced vascular changes is unknown. To investigate the hypothesis that As(III) targets the hepatic endothelium to initiate pathogenic change, mice were exposed to 0 or 250 parts per billion (ppb) of As(III) in their drinking water for 5 weeks. Arsenic(III) exposure did not affect the overall health of the animals, the general structure of the liver, or hepatocyte morphology. There was no change in the total tissue arsenic levels, indicating that arsenic does not accumulate in the liver at this level of exposure. However, there was significant vascular remodeling with increased sinusoidal endothelial cell (SEC) capillarization, vascularization of the peribiliary vascular plexus (PBVP), and constriction of hepatic arterioles in As(III)-exposed mice. In addition to ultrastructural demonstration of SEC defenestration and capillarization, quantitative immunofluorescence analysis revealed increased sinusoidal PECAM-1 and laminin-1 protein expression, suggesting gain of adherens junctions and a basement membrane. Conversion of SECs to a capillarized, dedifferentiated endothelium was confirmed at the cellular level with demonstration of increased caveolin-1 expression and SEC caveolae, as well as increased membrane-bound Rac1-GTPase. CONCLUSION: These data demonstrate that exposure to As(III) causes functional changes in SEC signaling for sinusoidal capillarization that may be initial events in pathogenic changes in the liver.

Animals↗

Capillarity and diffusion distances in skeletal muscles in birds.

Tissue capillarity and diffusion distances were determined for red and white skeletal muscles of adult birds ranging in mass from 10.8 to 6200 g. In addition, literature values for capillarity and diffusion distances in skeletal muscles of mammals were incorporated into the data set. Muscle mass was closely coupled to body mass. However, no significant allometric relations were found for any of the other variables measured. Number of capillaries per fiber was not correlated with cross sectional area of individual muscle fibers. Thus, capillary density decreased in a hyperbolic manner against fiber area and diffusion distance decreased in a hyperbolic manner against the number of capillaries per muscle fiber. Red muscles had significantly higher numbers of capillaries per fiber and significantly shorter diffusion distances than did white muscles. The patterns for tissue capillarity and diffusion distances in avian muscle reported here are similar to values reported previously for mammalian muscles. In both taxonomic groups capillarity and diffusion distances are independent of body mass. In addition, diffusion distances are characteristic of capillaries distributed in random arrays through the muscle cross section.

Animals↗