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1.
Hypertension ; 30(2 Pt 1): 272-7, 1997 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-9260992

RESUMO

Several studies have demonstrated the effectiveness of angiotensin I-converting enzyme (ACE) inhibitors in preventing the neointima formation found after denudation of the rat carotid artery by balloon injury. The aim of the present study was to determine the role of ACE in this model and to compare the treatment with the ACE inhibitor ramiprilat with that with the angiotensin II antagonist HR 720. The endothelial layer of the left carotid artery was removed using an inflated balloon catheter. Injured and control vessels were both submitted to histomorphological analysis and DNA content quantification at 2, 4, 6, 8, 12, and 14 days after injury. Evaluation of neointima thickening demonstrated a slow but steady increase of neointima that was significant after day 6 and reached 30% of the lumen in 2 weeks. This was paralleled by an increase in DNA content, which was significant 4 days after injury. ACE mRNA levels were quantified by polymerase chain reaction after reverse transcription. Measurement of ACE mRNA levels revealed a significant upregulation 2 and 8 days after injury, with no significant difference when compared with control tissue at later time points. ACE activity was also significantly enhanced at 2 and 8 days after injury, with no significant difference when compared with control tissue at later time points. In addition, the treatment with ramiprilat was more efficient in reducing neointima formation than that with HR 720. These data underlie the role of ACE in this model of restenosis. The early induction of ACE expression after endothelial injury but before significant changes in the vessel structure suggests that ACE activity might be one of the mechanisms that trigger neointima formation in the rat.


Assuntos
Artérias Carótidas/enzimologia , Lesões das Artérias Carótidas , Cateterismo , Peptidil Dipeptidase A/metabolismo , Ferimentos não Penetrantes/enzimologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Arteriopatias Oclusivas/prevenção & controle , Compostos de Bifenilo/farmacologia , Artérias Carótidas/patologia , DNA/metabolismo , Indução Enzimática , Imidazóis/farmacologia , Masculino , Peptidil Dipeptidase A/genética , Reação em Cadeia da Polimerase , RNA Mensageiro/metabolismo , Ramipril/análogos & derivados , Ramipril/farmacologia , Ratos , Ratos Sprague-Dawley , Túnica Íntima/efeitos dos fármacos , Túnica Íntima/patologia , Ferimentos não Penetrantes/patologia
2.
Lab Invest ; 75(2): 273-80, 1996 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-8765327

RESUMO

The possibility that polymorphonuclear leukocytes (PMN) recruited into the lung have the capability to damage alveolar septa was investigated in several strains of mice with different serum alpha 1 proteinase inhibitor levels and PMN lysosomal functions. After an intratracheal instillation of FMLP (200 micrograms), all strains of mice showed a similar PMN influx in alveolar spaces with an increase (approximately 4- to 5-fold) in bronchoalveolar lavage total cell count, which peaked at 24 to 48 hours. At this time, differential cell count in all strains revealed an approximately 40-fold increase in neutrophils. In C57BL/6J and pallid mice but not in NMRI mice, PMN influx was followed by a decrease in lung elastin content (-17% and -37%, respectively) and by the development of significant emphysema (mean linear intercept, +28% and +56%, respectively). The onset of the pulmonary lesion was preceded by a marked increase of neutrophil elastase burden in alveolar interstitium. Compared with NMRI mice, C57BL/6J and pallid mice have lower serum elastase inhibitory capacity levels. The degree of lung destruction was inversely correlated with elastase inhibitory capacity levels. Lung elastin degradation and emphysema may be induced by eliciting PMN into the lungs only in animals with a deficient anti-elastase screen. Compared with C57BL/6J mice, pallid mice showed a significantly greater lung elastin loss and a higher degree of emphysema after FMLP treatment. These differences may be accounted for by the higher baseline levels of interstitial elastase burden. It may be assumed that an enzymatically active elastase was already working on the lung interstitium before FMLP instillation in pallid mice.


Assuntos
Quimiotaxia de Leucócito , Elastina/biossíntese , Elastase de Leucócito/sangue , Pulmão/enzimologia , Pulmão/patologia , Neutrófilos/enzimologia , Neutrófilos/patologia , Elastase Pancreática/sangue , Enfisema Pulmonar/enzimologia , Enfisema Pulmonar/patologia , Deficiência de alfa 1-Antitripsina , Animais , Líquido da Lavagem Broncoalveolar/citologia , Elastase de Leucócito/metabolismo , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Neutrófilos/metabolismo , Elastase Pancreática/metabolismo , Enfisema Pulmonar/metabolismo , alfa 1-Antitripsina/genética
3.
Br J Clin Pract Suppl ; 84: 1-10, 1996 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-8994995

RESUMO

The effect of chronic oral treatment with the angiotensin converting enzyme (ACE) inhibitor ramipril at antihypertensive and sub-antihypertensive doses, on vascular morphology and function as well as left ventricular hypertrophy (LVH) and cardiac capillary length density was investigated in spontaneously hypertensive rats (SHR). Treatment was commenced before hypertension developed (prevention study) or in adult animals with established hypertension (regression study). In both studies, high-dose ramipril reduced ACE activity in plasma, heart and aorta, normalised blood pressure, and prevented LVH or caused regression of LVH. Low-dose ramipril did not prevent the development of hypertension or LVH, but caused an increase in cardiac capillary length density. In adult hypertensive animals, low-dose ramipril did not reduce blood pressure but caused regression of LVH. In both studies, vascular function as tested in the aortic vessels was improved not only after high- but also after low-dose ACE inhibitor treatment: an inhibition of vascular ACE was associated with attenuated vasoconstrictor responses to norepinephrine and enhanced dilator responses to acetylcholine and bradykinin. A reduction of vascular hypertrophy/hyperplasia in the mesenteric vessels was achieved by the antihypertensive dose of ramipril in the prevention but not the regression study. Our data demonstrate that an improvement of vascular function in SHR can be achieved by chronic ACE inhibition with ramipril independently of structural changes and of the antihypertensive action exerted by the drug. LVH was reduced even at a sub-antihypertensive dose of ramipril in the regression but not the prevention study. In the prevention study, however, low-dose ramipril, like high-dose ramipril, was able to protect the heart by preventing cardiac microvascular rarefaction.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Hipertensão/tratamento farmacológico , Ramipril/uso terapêutico , Acetilcolina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Aorta/enzimologia , Bradicinina/farmacologia , Hipertensão/enzimologia , Hipertensão/prevenção & controle , Hipertrofia Ventricular Esquerda/enzimologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Técnicas In Vitro , Artérias Mesentéricas/anatomia & histologia , Artérias Mesentéricas/efeitos dos fármacos , Miocárdio/enzimologia , Norepinefrina/farmacologia , Peptidil Dipeptidase A/metabolismo , Ramipril/farmacologia , Ratos , Ratos Endogâmicos SHR , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Vasodilatadores/farmacologia
4.
Lab Invest ; 74(2): 353-62, 1996 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-8780155

RESUMO

Three mutants of the C57 BL/6J strain, i.e., the tight-skin (Tsk), pallid (pa), and beige (bg) mice have been reported to develop spontaneous emphysema. However, the pathogenic mechanisms of this lesion may be different in the three mutants. Differences and similarities of these models were investigated by means of scanning electron microscopy. A light microscopic investigation provided the background for the SEM study. C57 BL/6J (control), pa, Tsk, and bg mice were killed when they were 1, 12, and 24 months old. At light microscopic investigation the lungs of the controls appeared normal at all ages. Those of the pa mice had normal appearance at 1 month, showed a few areas of air space enlargement with destruction of alveolar septa at 12 months, and had a generalized enlargement of the air spaces associated with distortion of alveolar septa at 24 months. The Tsk mice had a generalized panlobular emphysema at all ages. The lungs of the bg mice showed at all ages a generalized enlargement of the air spaces not accompanied by changes of the alveolar septa. At scanning electron microscopy the lung parenchyma of control mice was essentially normal at all ages. Both alveolar ducts and alveoli increased in size (the latter also in depth) with age. The number of interalveolar pores (Np) increased by 54% between 1 and 12 months of age and by 49% between 12 and 24 months. The parenchyma of pa mice did not differ significantly from that of the controls at 1 month. At 12 months the alveoli appeared to be larger. At 24 months in some fields alveolar ducts were enlarged, the alveoli were also enlarged and very shallow. Np was not different from controls at 1 month but greater at 12 (+ 49%) and 24 (+ 26%) months. The parenchyma of Tsk mice of all ages appeared distorted with enlargement of alveolar ducts and sacs and with alveoli with a large number of pores. These changes increased with age. Np was larger than the controls at all ages (+ 59% at 1 month, + 119% at 12 months, and + 80% at 24 months). The parenchyma of the bg mice of all ages appeared disorganized with large alveoli of different shapes. There was a deterioration with age. No difference in Np was seen at any age between bg and control mice. Parenchymal changes characterized by distortion and enlargement of alveolar ducts and sacs were observed, even if with different onset and extent, in all mutants. However, an increase in Np, which is considered to represent the early development of emphysema, was found only in Tsk and pa mice. In Tsk mice, high Np values were observed at all ages, whereas in pa mice Np was increased only late in life when the pulmonary lesion develops. These differences indicate different pathogenetic mechanisms for these three mutants.


Assuntos
Camundongos Endogâmicos C57BL/genética , Mutação , Enfisema Pulmonar/genética , Envelhecimento/fisiologia , Animais , Animais Recém-Nascidos/crescimento & desenvolvimento , Pulmão/patologia , Camundongos , Microscopia Eletrônica de Varredura , Alvéolos Pulmonares/ultraestrutura , Enfisema Pulmonar/patologia
5.
Exp Mol Pathol ; 60(2): 100-7, 1994 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-8070538

RESUMO

The tight-skin (Tsk) mouse is a genetic model of pulmonary emphysema. In this mouse, right ventricular hypertrophy (RVH) starts to develop at approximately 8 months of age, probably as a consequence of the emphysema. The aim of the present study was to investigate cardiac collagen synthesis, content, and types both before and during the development of RVH. Collagen synthesis, assessed by the [3H]proline incorporation method, was significantly increased in the right ventricle of 3-month-old Tsk mice. This was accompanied by a marked increase in right ventricle collagen content. Collagen typing showed no difference from controls. At 8 months of age collagen synthesis had returned to control values, right ventricular collagen content was elevated but held lower values than at 3 months, and collagen typing showed a prevalence of the more compliant type III. By 16 months of age, right ventricular collagen content had returned to control values and there was a shift in collagen types due to a relative increase of the more rigid type I. At 24 months of age right ventricular collagen content was increased again and collagen type I continued to predominate. These results suggest a dynamic role for collagen both before and during the development of RVH secondary to emphysema.


Assuntos
Colágeno/metabolismo , Hipertrofia Ventricular Direita/complicações , Hipertrofia Ventricular Direita/metabolismo , Miocárdio/metabolismo , Enfisema Pulmonar/complicações , Enfisema Pulmonar/embriologia , Animais , Colágeno/análise , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Miocárdio/química , Miocárdio/patologia , Tamanho do Órgão , Prolina/metabolismo , Biossíntese de Proteínas , Trítio
7.
Lab Invest ; 68(2): 233-41, 1993 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-8441253

RESUMO

BACKGROUND: The current hypothesis of pulmonary emphysema is based on an alteration of the protease-antiprotease balance within the lower respiratory tract. This hypothesis derives largely from studies in emphysema patients with genetic deficiency in serum alpha 1-antitrypsin. In animals, naturally occurring deficiency in serum elastase inhibitory capacity associated with early development of emphysema has been reported in the tight-skin mouse. We describe here a mouse model of genetic deficiency of alpha 1-antitrypsin in which emphysema occurs late in life. EXPERIMENTAL DESIGN: A genetic deficiency in serum alpha 1-antitrypsin was investigated in pallid mice, a strain with spontaneous occurring emphysema. Additionally, the possible pathogenetic role of an elastase-anti-elastase imbalance in pallid mice was investigated using molecular biologic, biochemical, histologic, ultrastructural, and immunoelectron microscopic methods. RESULTS: Pallid mice have markedly low levels of serum alpha 1-antitrypsin associated with a severe deficiency in serum elastase inhibitory capacity. However, they have normal alpha 1-antitrypsin mRNA levels in the liver. At ultrastructural examination, disruption of alveolar septa is first seen at 8 months of age. At histologic examination, some patchy areas of air-space enlargement with destruction of alveolar septa are seen from 12 months of age onward. These histologic changes are paralleled by a decrease in lung elastin content. The development of the pulmonary lesions is preceded by an alveolar elastolytic burden detected by an immunogold technique. CONCLUSIONS: All these data suggest that the lung changes in pallid mice are the result of an elastolytic process due to a severe inborn deficiency of serum alpha 1-antitrypsin. This animal model reproduces important features of the human condition and may provide new insights into the pathogenesis of emphysema.


Assuntos
Modelos Animais de Doenças , Enfisema Pulmonar/etiologia , Deficiência de alfa 1-Antitripsina , Animais , Sequência de Bases , Elastina/análise , Pulmão/química , Pulmão/patologia , Pulmão/ultraestrutura , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microscopia Eletrônica , Microscopia Imunoeletrônica , Dados de Sequência Molecular , Elastase Pancreática/análise , Elastase Pancreática/antagonistas & inibidores , Elastase Pancreática/imunologia , Alvéolos Pulmonares/ultraestrutura , Enfisema Pulmonar/patologia , alfa 1-Antitripsina/genética
8.
J Hypertens Suppl ; 10(6): S141-4, 1992 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-1432317

RESUMO

AIM: We performed two sets of experiments in order to prevent or to regress cardiac and vascular hypertrophy, using antihypertensive and subantihypertensive doses of the angiotensin converting enzyme inhibitor zabicipril. METHODS AND RESULTS: Spontaneously hypertensive rats (SHR) begin to develop hypertension at less than 4 weeks of age and reach stable hypertension levels after 12-14 weeks. The blood pressure increase is accompanied by the development of cardiac and vascular hypertrophy. Treatment of SHR in utero and up to the age of 20 weeks with an antihypertensive dose of zabicipril (1 mg/kg per day) not only prevented the development of high blood pressure but also the development of cardiac and vascular hypertrophy. This effect was demonstrated by a significant decrease in left ventricular weight and the number of smooth muscle cell layers in the vascular media, media thickness and the media:lumen ratio in mesenteric arteries. In contrast, antihypertensive treatment with the Ca2+ antagonist verapamil (100 mg/kg per day) and the subantihypertensive dose of zabicipril (0.01 mg/kg per day) did not affect the development of cardiac and vascular hypertrophy. We found a significant increase in the length and surface density of myocardial capillaries after treatment with zabicipril at 1 mg/kg per day, indicating that the capillary density had improved and therefore that the oxygen supply of the heart was improved. Similar findings were observed with the low dose of zabicipril in SHR, although these rats had high blood pressure and cardiac and vascular hypertrophy. CONCLUSIONS: Treatment of adult SHR for 16 weeks with zabicipril at 1 mg/kg per day completely normalized their blood pressure levels. This effect was accompanied by a regression of left ventricular but not of vascular hypertrophy. Treatment with an antihypertensive dose of verapamil or with a subantihypertensive dose of zabicipril had no effect on cardiac and vascular hypertrophy.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes , Compostos Bicíclicos com Pontes/farmacologia , Vasos Coronários/efeitos dos fármacos , Hipertensão/prevenção & controle , Hipertrofia Ventricular Esquerda/prevenção & controle , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Animais Recém-Nascidos , Compostos Bicíclicos com Pontes/administração & dosagem , Compostos Bicíclicos com Pontes/uso terapêutico , Capilares/efeitos dos fármacos , Capilares/patologia , Vasos Coronários/patologia , Coração Fetal/efeitos dos fármacos , Feto/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipertrofia/prevenção & controle , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Ratos , Ratos Endogâmicos SHR , Verapamil/farmacologia , Verapamil/uso terapêutico
9.
Exp Mol Pathol ; 56(2): 163-72, 1992 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-1587342

RESUMO

The tight-skin (Tsk) mouse is a genetic model of pulmonary emphysema linked to a deficiency of serum antielastase. In this mouse occurrence of connective tissue abnormalities in various organs (systemic scleroderma) has been reported. The aim of the present work was to study lung collagen synthesis and deposition in Tsk mice. No differences in the collagen synthesis rate and morphology at the ultrastructural level were found in Tsk mice at birth. At 2 months of age, a marked increase in collagen was observed within the alveolar septa. At this time, an increased lung collagen synthesis, assessed by determining prolyl hydroxylase activity and incorporation of radiolabeled proline, was found in Tsk mice with respect to control mice. However, due to the ongoing parenchymal destruction, the values of total lung collagen at 6 and 12 months of age were only moderately but significantly increased with respect to those observed at 2 months. As a consequence, a progressive accumulation of lung collagen fibers was observed in the residual septa. The increase in collagen deposition was accompanied by a relative increase in type I collagen. Although the data in the literature would suggest a genetic cause for the lung collagen change in Tsk mice, the data presented here indicate that the change in lung collagen metabolism may be a part of a remodeling process taking place after lung destruction.


Assuntos
Colágeno/metabolismo , Enfisema/genética , Enfisema/metabolismo , Pulmão/metabolismo , Animais , Modelos Animais de Doenças , Enfisema/patologia , Feminino , Pulmão/patologia , Pulmão/ultraestrutura , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Microscopia Eletrônica , Modelos Genéticos , Prolina/metabolismo , Trítio
12.
Am Rev Respir Dis ; 142(2): 333-7, 1990 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-2143363

RESUMO

The causes for the development of right ventricular hypertrophy (RVH) in emphysema are not fully understood. In the 1960s, studies of RVH in association with emphysema found no correlation between the extent of tissue damage in the lung and the RV weight. This was thought to disprove the theory that the RVH was due to an increase in pulmonary vascular resistance secondary to capillary destruction. In the present study, the development of RVH was investigated in tight-skin (tsk) mice with genetic emphysema. RVH started to develop in mature to senescent animals between 8 and 16 months of age and progressed thereafter. At 24 months of age, RV weight and the ratios RV/body weight and RV/LV + S weight were, respectively, 52, 96, and 60% greater than in control (pa) mice. At this time blood gas analysis revealed hypoxemia in tsk but not in pa mice. The mean linear intercept of tsk mice was 83% larger and the surface area of the walls of distal air spaces per unit lung volume was 40% smaller than in pa mice. There was a strong correlation between the severity of emphysema, assessed by both techniques, and the RV/LV + S ratio (p less than 0.001 for both). No muscularized arterioles were seen in the tsk mice, and the medial thickness of muscular arteries was almost identical in the two groups. This demonstrates that in emphysema, RVH can develop in the absence of pulmonary vascular changes and is probably due to tissue (and thus capillary) destruction.


Assuntos
Cardiomegalia/etiologia , Enfisema Pulmonar/genética , Animais , Arteríolas/patologia , Gasometria , Feminino , Hipertrofia , Masculino , Camundongos , Camundongos Mutantes , Artéria Pulmonar/patologia , Enfisema Pulmonar/complicações , Enfisema Pulmonar/patologia , Resistência Vascular
13.
Exp Mol Pathol ; 52(1): 46-53, 1990 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-2307213

RESUMO

The tight-skin (Tsk) mouse is a model of genetically determined emphysema. The cause for the development of the lung lesion is unknown. In the present study we investigated the lung morphometry and the serum elastase inhibitory capacity (EIC) of Tsk mice. Mean interalveolar distance was significantly greater (+60%) in Tsk mice than in C57 Bl/6J, NMRI, and Balb/c mice, which have similar values. Serum of Tsk mice against mouse leukocyte elastase (MLE) has significantly lower EIC values than that of NMRI, Balb/c (-64%), and C57 Bl/6J (-50%) mice. Similar results were obtained when porcine pancreatic elastase (PPE) was used. Against human leukocyte elastase (HLE), however, there was no difference among the strains, all of which had high EIC values. Preincubation of mouse (C57 Bl/6J) serum with chloramine-T (CT) resulted in an almost complete inhibition of EIC against MLE and PPE but only in a 20% inhibition against HLE using a synthetic substrate. Using elastin Congo Red as substrate, CT inhibited EIC against MLE and PPE by approximately 70% but did not affect the EIC against HLE. These results indicate that (1) the Tsk mouse can be considered a model of severe inborn deficiency of serum antielastase activity which is associated with emphysema; and (2) MLE and PPE can be considered interchangeable in studies of serum EIC in the mouse. On the other hand, the differences between MLE and HLE preclude the use of HLE for EIC determination in this species.


Assuntos
Enfisema/sangue , Camundongos Mutantes/genética , Elastase Pancreática/antagonistas & inibidores , Inibidores de Serina Proteinase/sangue , Serpinas , Animais , Cloraminas/farmacologia , Enfisema/genética , Elastase de Leucócito , Masculino , Camundongos , Elastase Pancreática/sangue , Elastase Pancreática/deficiência , Elastase Pancreática/imunologia , Inibidores de Serina Proteinase/imunologia
14.
Exp Mol Pathol ; 51(1): 18-30, 1989 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-2767216

RESUMO

The tight-skin (Tsk) mouse has recently been proposed as a genetic model of emphysema. A morphometric study has shown that emphysema develops quickly, between 15 days and 1 month after birth. Previous biochemical and ultrastructural investigations of the lungs of 1- and 2-month-old Tsk mice revealed the presence of an ongoing elastolytic process. The goal of the present study was to investigate the role of mouse leukocyte elastase (MLE) in the development of emphysema in 1-month-old Tsk mice. Using electron microscopy and an immunogold labeling technique with rabbit anti-MLE IgG, MLE was localized within the lung neutrophils of control and Tsk mice. MLE was also found associated with elastin in the alveolar septa of Tsk but not of control mice. Little or no labeling was associated with other components (collagen, pneumocytes, and endothelium) of alveolar septa of Tsk mice. Lung elastin of control mice, or of control mice rendered emphysematous with porcine pancreatic elastase, showed negligible gold particle density when incubated with gold-conjugated rabbit IgG. Thus, under the present experimental conditions, an aspecific labeling of elastin is unlikely. This study indicates that MLE may be one of the factors responsible for the rapid development of emphysema in Tsk mice.


Assuntos
Pulmão/enzimologia , Camundongos Mutantes/metabolismo , Elastase Pancreática/metabolismo , Enfisema Pulmonar/enzimologia , Animais , Tecido Conjuntivo/enzimologia , Imuno-Histoquímica , Camundongos , Microscopia Eletrônica
15.
Exp Mol Pathol ; 50(3): 398-410, 1989 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-2721656

RESUMO

The tight-skin (Tsk) mouse has recently been proposed as a genetic model of emphysema. In the present study, the development of emphysema was investigated in these mice with histological, biochemical, and ultrastructural methods at 4 days and at 1 and 2 months of life. At 4 days after birth, histological examination of the lungs revealed only a mild enlargement of the primary sacculi. Neither biochemical nor ultrastructural changes were seen however at this time. At 1 month of age, the histological examination showed marked emphysema-like changes, characterized by enlargment of air spaces accompanied by destruction of alveolar walls. Biochemical analysis showed a marked decrease in insoluble elastin content and a significant increase in salt-extractable collagen. Ultrastructural investigation revealed edema fluid in the interstitium and broken and disorganized elastic fibers. All these findings strikingly resemble the changes which occur in the lungs early after an instillation of elastase. In the 2-month-old Tsk mice the histological lesion progressed in severity. The ultrastructural findings were similar to those observed at 1 month, and the biochemical changes showed no signs of recovery. Thus, in these mice, the emphysematous lesion develops very rapidly between 4 days and 1 month of life and shows the characteristics of an elastolytic process which is still ongoing at 2 months of age.


Assuntos
Enfisema/etiologia , Pulmão/patologia , Animais , Colágeno/análise , Modelos Animais de Doenças , Elastina/análise , Enfisema/genética , Enfisema/patologia , Feminino , Pulmão/análise , Pulmão/ultraestrutura , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica
16.
Am Rev Respir Dis ; 139(1): 226-32, 1989 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-2912343

RESUMO

The tight-skin (tsk) mouse has been recently proposed as a model of genetically determined emphysema. In the present study, the development of this lung lesion was investigated morphometrically in both male and female tsk mice from 4 days to 16 months of age. "Pallid" (pa) mice with a closely related genetic background served as controls. Despite small differences in the mean linear intercept seen at 1 and at 16 months, both male and female tsk mice were found to be similarly susceptible to the development of the emphysematous lesion. Three main phases were observed in the evolution of the emphysema. The first phase, from 4 days to 2 months after birth, included enlargement of the peripheral lung units, already evident at 4 and at 15 days, and destruction of the lung parenchyma, which occurred between 15 days and 1 month and rapidly progressed for as long as 2 months. A second phase of stabilization or of mild progression of the emphysematous lesion occurred between 2 and 8 months of age. A third phase, in the advanced age between 8 and 16 months, included a further exacerbation of the parenchymal destruction. At 16 months of age, the lungs of the pa mice also showed some patchy areas of air-space enlargement with destruction of the alveolar septa.


Assuntos
Enfisema Pulmonar/genética , Animais , Feminino , Pulmão/patologia , Medidas de Volume Pulmonar , Masculino , Camundongos , Camundongos Mutantes , Enfisema Pulmonar/patologia , Enfisema Pulmonar/fisiopatologia
17.
Am Rev Respir Dis ; 134(3): 580-4, 1986 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-3752713

RESUMO

An ultrastructural study of the myocardium in control dogs and in dogs with papain-induced emphysema of 6 months duration without signs of right ventricular hypertrophy was undertaken to determine the number, size, and relative volume of the mitochondria. In the right ventricle of the emphysematous dogs, the number of mitochondrial profiles was greater per unit area of tissue (46.18 +/- 1.28/100 micron 2 versus 41.20 +/- 1.60/100 micron 2, p less than 0.05), but the mitochondria were smaller in size (mean mitochondrial profile area: 0.39 +/- 0.01 micron 2 versus 0.46 +/- 0.02 micron 2, p less than 0.05; mean mitochondrial "diameter": 0.65 +/- 0.01 micron versus 0.71 +/- 0.02 micron, p less than 0.05) than in control dogs. A highly significant negative correlation was found in the right ventricle of control and emphysematous dogs between the number per unit area and the size (area) of the mitochondrial profiles (r = -0.92; p less than 0.001). The increase in number but decrease in size of the mitochondrial profiles resulted in an unchanged relative volume of mitochondria in the right ventricle of the emphysematous dogs. In the subendocardium and in the subepicardium of the left ventricle of the papain-treated dogs, these changes were smaller and did not reach significance. These ultrastructural changes in the myocardium of the emphysematous animals are considered to be a response to a situation of prolonged increase in work of the right ventricle and may represent an early stage of a developing right ventricular hypertrophy.


Assuntos
Mitocôndrias Cardíacas/ultraestrutura , Enfisema Pulmonar/patologia , Animais , Cães , Endocárdio/ultraestrutura , Ventrículos do Coração/ultraestrutura , Pericárdio/ultraestrutura
18.
Lab Invest ; 50(5): 592-6, 1984 May.
Artigo em Inglês | MEDLINE | ID: mdl-6232425

RESUMO

In the hearts of control beagle dogs, capillary density in the right ventricle was found to be similar to that of the subendocardium of the left ventricle but lower than that of the subepicardium of the left ventricle. In emphysematous animals, 6 months after the exposure to papain (the emphysema-inducing agent), capillary density in the right ventricle and in the subendocardium of the left ventricle increased significantly, reaching values similar to that of the subepicardium of the left ventricle, which remained constant. These morphologic changes are considered to be an adaptation to a prolonged condition of increased myocardial oxygen demand and/or may represent an early stage of a developing cardiac hypertrophy.


Assuntos
Vasos Coronários/patologia , Enfisema/patologia , Animais , Capilares/patologia , Cardiomegalia , Cães , Ventrículos do Coração/patologia , Microscopia Eletrônica
19.
Am Rev Respir Dis ; 126(5): 898-903, 1982 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-6816111

RESUMO

The development of papain-induced emphysema and the effect of structural changes of the lung on pulmonary hemodynamics were investigated in the dog in a 6-month study. Papain was administered as an aerosol at the beginning of the study and at Day 21; control animals received saline. At 3 or at 6 months, hemodynamic investigations were carried out in the awake animal (sedated with piritramide). The dogs were then killed and the lungs processed for morphometric evaluation. Arterial blood gases were analyzed at regular intervals for the duration of the study. In the papain-treated dogs, mean linear intercept (Lm) and internal surface area of the lungs corrected to an arbitrary lung volume of 2L (ISA2) were significantly different from control dogs both at 3 and at 6 months. No progression of the structural changes of the lung occurred between these two time intervals. Arterial blood oxygenation was normal throughout the study. In the papain-treated group at 6, but not at 3, months, mean pulmonary arterial blood pressure (PAPm) and pulmonary arteriolar resistance (PAR) were significantly augmented when compared with the control group. A significant correlation was found at 6 months between the Lm and ISA2 on one side, and PAPm and PAR on the other side, suggesting that the structural changes of the lung were responsible for pulmonary hemodynamic alterations.


Assuntos
Pulmão/patologia , Papaína , Circulação Pulmonar , Enfisema Pulmonar/induzido quimicamente , Aerossóis , Animais , Peso Corporal , Dióxido de Carbono/sangue , Cães , Feminino , Medidas de Volume Pulmonar , Masculino , Tamanho do Órgão , Oxigênio/sangue , Artéria Pulmonar/patologia , Enfisema Pulmonar/patologia , Enfisema Pulmonar/fisiopatologia , Fatores de Tempo
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