1,720,971 research outputs found
A 16-month study of the development of genetic emphysema in tight-skin mice
No full textThe 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
Tsk mice with genetic emphysema. Right ventricular hypertrophy occurs without hypertrophy of muscular pulmonary arteries or muscularization of arterioles
No full textThe 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
Neutrophil recruitment into the lungs is associated with increased lung elastase burden, decreased lung elastin, and emphysema in alpha1-proteinase inhibitor deficient mice
No full textThe 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
Development of emphysema in two mouse strains with genetic serum antielastase deficiency
No full textA scanning electron microscopic investigation of genetic emphysema in tight-skin, pallid, and beige mice, three different C57 Bl/6J mutants
No full textThree 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
Studio di due modelli genetici di enfisema polmonare associati a carenza di alfa-1-antiproteinasi
No full textChanges in collagen metabolism in the right ventricle precede right ventricular hypertrophy in Tsk mice with genetic emphysema
No full textImmunoelectron-microscopic demonstration of elastase in emphysematous lungs of tight-skin mice
No full textThe 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
A biochemical and morphological investigation of the early development of genetic emphysema in tight-skin mice
No full textThe 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 ag
- …
