Morphological and biochemical features of elastase-induced emphysema in strain AJ mice

doi:10.1016/0041-008X(83)90290-9

Toxicology and Applied Pharmacology

Volume 68, Issue 3, May 1983, Pages 451-461

https://doi.org/10.1016/0041-008X(83)90290-9 Get rights and content

Abstract

Elastase-induced animal models of pulmonary emphysema are potentially useful to study the physiological, anatomical, and biochemical injuries associated with emphysema. After the endotracheal instillation of porcine pancreatic elastase (0.15 or 0.30 mg elastase per 100 g body weight) into strain $A J$ mice, selected biochemical and morphometric indices of lung damage were examined. Elastase produced extensive air enlargement without appreciable mortality. Lesions involving the lung parenchyma distal to the terminal bronchioles were observed within 2 weeks and possessed features resembling panlobular and centrilobular emphysema. Morphometric analyses of emphysema indicated that after the acute phase of tissue damage and repair, the lesions stabilize without further deterioration of alveolar structure. Increased lung elastin synthesis was noted following endotracheal elastase, resulting in lung elastin levels 30% higher than controls 8 weeks after treatment. Minimal alterations to lung DNA and protein levels indicated that elastase produced specific lung lesions exclusive of inflammation and edema.

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Cited by (22)

Quantitative assessment of regional lung ventilation in emphysematous mice using hyperpolarized <sup>129</sup>Xe MRI with a continuous flow hyperpolarizing system
2022, Magnetic Resonance Imaging
Citation Excerpt :
For each mouse, the standard SR and LL-SR sequences in spectroscopy and imaging modes were implemented five, five, and three times, respectively, to obtain averages and standard errors for the parameters determined. The emphysematous mice were prepared by instilling porcine pancreatic elastase (PPE) from Wako Pure Chemical Industries, Ltd., Japan at 300 U/100 gBW [23]. PPE was dissolved in a phosphate-buffered saline and instilled intravenously at a concentration of 12 U/ml.
Lung ventilation function in small animals can be assessed by using hyperpolarized gas MRI. For these experiments a free breathing protocol is generally preferred to mechanical ventilation as mechanical ventilation can often lead to ventilation lung injury, while the need to maintain a gas reservoir may lead to a partial reduction of the polarization.
To evaluate regional lung ventilation of mice by a simple but fast method under free breathing and give evidence for effectiveness with an elastase instilled emphysematous mice.
Emphysematous mice.
A Look-Locker based saturation recovery sequence was developed for continuous flow hyperpolarized (CF-HP) ¹²⁹Xe gas experiments, and the apparent gas-exchange rate, k’, was measured by the analysis of the saturation recovery curve.
In mice with elastase-induced mild emphysema, reductions of 15–30% in k’ values were observed as the results of lesion-induced changes in the lung.
The proposed method was applied to an emphysematous model mice and ventilation dysfunctions have been approved as a definite decrease in k’ values, supporting the usefulness for a non-invasive assessment of the lung functions in preclinical study by the CF-HP ¹²⁹Xe experiments.
Alterations in pulmonary structure by elastase administration in a model of emphysema in mice is associated with functional disturbances
2012, Revista Portuguesa de Pneumologia
Citation Excerpt :
These include enzyme airway administration model,7,8 tobacco smoking model,9,10 apoptosis induced emphysema by intratracheal instillation of activated caspase-3,11 AIAT deficient animals,12 natural mutants,13 knockout mice,14 and transgenic mice.15 Despite the model chosen all of them present restrictions.16–22 Taking these informations into account, in the present study we chose to reproduce human pulmonary emphysema in mouse model using intratracheal instillation of porcine pancreatic elastase because it is used for more than three decades and has been well characterized.29
Several experimental studies of pulmonary emphysema using animal models have been described in the literature. However, only a few of these studies have focused on the assessment of ergometric function as a non-invasive technique to validate the methodology used for induction of experimental emphysema. Additionally, functional assessments of emphysema are rarely correlated with morphological pulmonary abnormalities caused by induced emphysema. The present study aimed to evaluate the effects of elastase administered by tracheal puncture on pulmonary parenchyma and their corresponding functional impairment. This was evaluated by measuring exercise capacity in C57Bl/6 mice in order to establish a reproducible and safe methodology of inducing experimental emphysema. Thirty six mice underwent ergometric tests before and 28 days after elastase administration. Pancreatic porcine elastase solution was administered by tracheal puncture, which resulted in a significantly decreased exercise capacity, shown by a shorter distance run (−30.5%) and a lower mean velocity (−15%), as well as in failure to increase the elimination of carbon dioxide. The mean linear intercept increased significantly by 50% in tracheal elastase administration. In conclusion, application of elastase by tracheal function in C57Bl/6 induces emphysema, as validated by morphometric analyses, and resulted in a significantly lower exercise capacity, while resulting in a low mortality rate.
Vários estudos experimentais de enfisema pulmonar em modelos animais têm sido descritos na literatura científica. No entanto, apenas alguns destes estudos têm sido concentrados na avaliação da função ergométrica como técnica não-invasiva para validar a metodologia utilizada para a indução do enfisema experimental. Além disso, as avaliações funcionais de enfisema raramente se encontram correlacionadas com anomalias morfológicas pulmonares causadas por enfisema induzido. O presente estudo teve como objetivo avaliar os efeitos da elastase administrada por punção traqueal no parênquima pulmonar e a sua disfunção funcional correspondente. Esta foi avaliada através da medição da capacidade de exercício em ratos C57Bl/6, de forma a estabelecer uma metodologia reprodutível e segura de induzir o enfisema experimental. Trinta e seis ratos foram submetidos a testes ergométricos antes e 28 dias após a administração de elastase. A solução de elastase pancreática suína foi administrada por punção traqueal, o que resultou numa diminuição significativamente da capacidade de exercício, demonstrada pela diminuição da distância percorrida (menos de 30,5%) e por uma velocidade média inferior (menos de 15%), assim como pela incapacidade de aumentar a eliminação de dióxido de carbono. A intersecção linear média aumentou significativamente em 50% na administração traqueal da elastase. Em conclusão, a aplicação de elastase por punção traqueal em ratos C57Bl/6 induz enfisema, conforme foi validado por análises morfométricas, e resultou numa capacidade de exercício significativamente mais baixa, embora se tenha obtido uma baixa taxa de mortalidade.
Murine models of COPD
2006, Pulmonary Pharmacology and Therapeutics
Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation, that is not fully reversible, and that is associated with an abnormal inflammatory response of the airways and lungs to noxious particles and gases. The airflow limitation is caused by increased resistance of the small conducting airways and by decreased elastic recoil forces of the lung due to emphysematous destruction of the lung parenchyma. In vivo animal models can help to unravel the molecular and cellular mechanisms underlying the pathogenesis of COPD. Mice represent the most favored animal species with regard to the study of (both innate and adaptive) immune mechanisms, since they offer the opportunity to manipulate gene expression. Several experimental approaches are applied in order to mimic the different traits of COPD in these murine models. Firstly, the tracheal instillation of tissue-degrading enzymes induces emphysema-like lesions in the lung parenchyma, adding further proof to the protease-antiprotease imbalance hypothesis. Secondly, the inhalation of noxious stimuli, including tobacco smoke, sulfur dioxide, nitrogen dioxide, or oxidants such as ozone, may also lead to COPD-like lesions in mice, depending on concentration, duration of exposure and strainspecific genetic susceptibility. Thirdly, in transgenic mice, a specific gene is either overexpressed (non-specific or organ-specific) or selectively depleted (constitutively or conditionally). The study of these transgenic mice, either per se or in combination with the above mentioned experimental approaches (e.g. the inhalation of tobacco smoke), can offer valuable information on both the physiological function of the gene of interest as well as the pathophysiological mechanisms of diseases with complex traits such as COPD.
A biochemical and morphological investigation of the early development of genetic emphysema in tight-skin mice
1989, Experimental and Molecular Pathology
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 emphysemalike changes, characterized by enlargement 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.
Pulmonary clearance of intratracheally administered <sup>63</sup>Ni<inf>3</inf>S<inf>2</inf> in strain A J mice
1984, Environmental Research
The pulmonary clearance of particulate ⁶³Ni₃S₂ was evaluated in strain $A J$ mice following the intratracheal instillation of 3 μCi of ⁶³Ni₃S₂ (1.66 μm, mass median diameter). Lung and tissue burdens were determined from serially sacrificed animals using scintillation counting techniques. Lung clearance over the 35-day observation period could be separated into two distinct components with initial and final phase biological half-times corresponding to 1.2 and 12.4 days, respectively. Radioactivity was detected in the blood, liver, kidney, and femur within 4 hr, and was eliminated at rates comparable to that in the lung. Excretion involved primarily urinary (60% of dose eliminated) but also fecal (40% of dose eliminated) pathways. The data are consistent with the relatively rapid translocation, solubilization, and elimination of particulate ⁶³Ni₃S₂ from the body.
Airway segmentation and analysis for the study of mouse models of lung disease using micro-CT
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^☆: Supported through Electric Power Research Institute Contract RP 1639.

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Morphological and biochemical features of elastase-induced emphysema in strain AJ mice☆

Abstract

Toxicol. Appl. Pharmacol.

J. Biol. Chem.

Anal. Biochem.

Alpha-1-antitrypsin deficiency and increased susceptibility to elastase-induced experimental emphysema in a rat model

Amer. Rev. Respir. Dis.

α-1-Antitrypsin in sera of inbred mice

Arch. Environ. Health

Morphological methods for evaluation of pulmonary toxicity in animals

Quantitative methods in the study of pulmonary pathology

Thorax

Studies in alpha-1-antitrypsin deficiency

Acta. Med. Scand.

Emphysema-like changes in the lungs of the blotchy mouse

Amer. Rev. Respir. Dis.

Experimental emphysema. Its production with papain in normal and silicotic rats

Arch. Environ. Health

The pathology of elastase-induced panacinar emphysema in hamsters

J. Pathol.

Intratracheal instillation methods for mouse lungs

Oncology

Effect of d1-penicillamine on elastic properties of rat lung

J. Appl. Physiol.

Prevention of elastase-induced experimental emphysema by oral administration of a synthetic elastase inhibitor

Amer. Rev. Respir. Dis.

The induction of emphysema with elastase. I. The evolution of the lesion and the influence of serum

J. Lab. Clin. Med.

Morphological and biochemical features of elastase-induced emphysema in strain $A J$ mice☆