Elastase-induced changes in lung function: relationship to morphometry and effect of drugs

Nishi, Yuhei; Boswell, Veronica D.; Ansari, Tahera; Piprawala, F; Satchi, S; Page, Clive

doi:10.1016/s1094-5539(03)00052-x

Cited by 30 publications

(20 citation statements)

References 17 publications

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“…As opposed to smoke-induced emphysema, it is relatively easy to produce severe emphysema with elastase instillation, and this facilitates detection of pulmonary function abnormalities, particularly when evaluating the effects of an inhibitor or intervention such as lung volume reduction surgery or abnormalities in connective tissue elasticity (15,51). Biochemical and in situ hybridization studies have shown that over time there is increased synthesis of elastin and to a lesser extent collagen (77), making the model a candidate for studies on alveolar repair and regeneration [however, studies using all trans retinoic acid and/or bone marrow cell instillation or various colony-stimulating factors to attempt to drive repair are contradictory (49,50,76,102,164)]. But probably the most important current reason to use the elastase emphysema model is the situation where an intervention requires scarce/expensive resources that would not be feasible for a 6-mo smoke exposure.…”

Section: Elastase Emphysema Modelmentioning

confidence: 99%

Animal models of chronic obstructive pulmonary disease

Wright¹,

Cosio²,

Churg³

2008

American Journal of Physiology-Lung Cellular and Molecular Phys

372

326

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-The mechanisms involved in the genesis of chronic obstructive pulmonary disease (COPD) are poorly defined. This area is complicated and difficult to model because COPD consists of four separate anatomic lesions (emphysema, small airway remodeling, pulmonary hypertension, and chronic bronchitis) and a functional lesion, acute exacerbation; moreover, the disease in humans develops over decades. This review discusses the various animal models that have been used to attempt to recreate human COPD and the advantages and disadvantages of each. None of the models reproduces the exact changes seen in humans, but cigarette smoke-induced disease appears to come the closest, and genetically modified animals also, in some instances, shed light on processes that appear to play a role. chronic obstructive pulmonary disease CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) is an increasingly important cause of morbidity and mortality. COPD is now the fifth leading cause of death worldwide (109), and recent estimates suggest that the prevalence is as high as 9 -10% of adults over age 40 (38, 131). In the developed world, cigarette smoking is by far the most important risk factor for COPD. Exposure to air pollution particles, occupational exposures to dusts and fumes (39), and, in the developing world, exposure to biomass fuels used for cooking is also believed to be etiological agents of COPD (38).There are few animal models of COPD related to air pollution particles, dusts and fumes, and biomass fuels; most COPD models have either used cigarette smoke or other approaches, including genetic modifications to mice, believed to reproduce some of the mechanisms behind cigarette smoke. We have recently reviewed mechanistic studies of smoke-exposed animal models (16). In this paper, we will focus on the pros and cons of different COPD animal models.The first question to ask in this context is what would constitute a perfect model of human COPD. This is not a simple question because human COPD consists of at least four anatomic lesions (further defined below): emphysema, small airway remodeling (including goblet cell metaplasia), chronic bronchitis, and pulmonary hypertension; a given patient may have any or all of these lesions. In addition, COPD patients may develop acute exacerbations that are believed to have an infectious basis. To further complicate matters, no matter which lesions are present, COPD develops and is slowly progressive over many years.Because COPD is closely related to the underlying anatomy of the lung, a good animal model should have pulmonary anatomy similar to that of humans. The fundamental mechanisms behind COPD should be similar in animal models and humans. The ideal model would allow the investigator to produce the various different anatomic lesions just listed, all in a short period of time. Unfortunately, all of the known animal models meet only some of the above criteria, and even another human would probably not meet all of them, because, as noted above, there is considerable human to human variation in th...

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Section: Elastase Emphysema Modelmentioning

confidence: 99%

Animal models of chronic obstructive pulmonary disease

Wright¹,

Cosio²,

Churg³

2008

American Journal of Physiology-Lung Cellular and Molecular Phys

372

326

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“…Serine proteinase inhibitors have also been shown to control abnormal exocytosis and secretion of endogenous proteinases which is characteristic of a number of diseases (Kennedy, 1998). The abnormal exocytosis of elastase, a serine proteinase from human neutrophil, is considered to be the primary source of tissue damage associated with inflammatory diseases as pulmonary emphysema (Janoff, 1985;Groutas, 1987;Fujita et al, 1990;Nishi et al, 2003;Ishizawa et al, 2004), adult respiratory distress syndrome (Lee et al, 1981;McGuire et al, 1982;Gossage et al, 1993;Yamazaki et al, 1999;Carney et al, 2001;Nakayama et al, 2002), septic shock (Uchida et al, 1995;Fujie et al, 1999;Dhainaut et al, 2001;Dhainaut, 2002;Devine, 2003), cystic fibrosis (O'Connor et al, 1993;Hansen et al, 1995;Lee and Downey, 2001;McGarvey et al, 2002;Greer et al, 2004), Chronic bronchitis (Fujita et al, 1990;Llewellyn-Jones et al, 1996;Moodley et al, 2000;Lai et al, 2004) and rheumatoid arthritis (Mohr and Wessinghage, 1983;Odagaki et al, 2001;Tur et al, 2004). Compounds which directly inhibit elastase or its release from human neutrophils are of increasing interest in the development of new anti-inflammatory drugs.…”

Section: Introductionmentioning

confidence: 99%

A serine proteinase inhibitor isolated from Tamarindus indica seeds and its effects on the release of human neutrophil elastase

et al. 2005

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Proteinaceous inhibitors with high inhibitory activities against human neutrophil elastase (HNE) were found in seeds of the Tamarind tree (Tamarindus indica). A serine proteinase inhibitor denoted PG50 was purified using ammonium sulphate and acetone precipitation followed by Sephacryl S-300 and Sephadex G-50 gel filtration chromatographies. Inhibitor PG50 showed a Mr of 14.9 K on Sephadex G-50 calibrated column and a Mr of 11.6 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. PG50 had selective activity while cysteine proteinases (papain and bromelain) and serine proteinases (porcine pancreatic elastase and bovine chymotrypsin) were not inhibited, it was strongly effective against serine proteinases such as bovine trypsin and isolated human neutrophil elastase. The IC50 value was determined to be 55.96 microg.mL-1. PG50 showed neither cytotoxic nor haemolytic activity on human blood cells. After pre-incubation of PG50 with cytochalasin B, the exocytosis of elastase was initiated using PAF and fMLP. PG50 exhibited different inhibition on elastase release by PAF, at 44.6% and on release by fMLP, at 28.4%. These results showed that PG50 preferentially affected elastase release by PAF stimuli and this may indicate selective inhibition on PAF receptors.

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“…Since that time, there have been a few studies, either by pathologic or physiologic assessment, that have bolstered this reported effect of ATRA on emphysema [2][3][4][5][6]. In contrast, a few experiments using any of a variety of animal models of emphysema demonstrated no beneficial effect of ATRA administration [7][8][9].…”

mentioning

confidence: 99%

INHALATION ADMINISTRATION OF ALL-TRANS-RETINOIC ACID FOR TREATMENT OF ELASTASE-INDUCED PULMONARY EMPHYSEMA IN FISCHER 344 RATS

March

Cossey

Esparza

et al. 2004

Experimental Lung Research

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A past study demonstrated that all-trans-retinoic acid (ATRA) treatment by intraperitoneal injection in a rat model of elastase-induced emphysema caused tissue regeneration as evidenced by a decrease in alveolar size and lung volume and an increase in alveolar number. We postulated that treatment with this retinoid by nose-only inhalation exposure would be a more efficient means of targeting damaged lung tissue. Emphysema was induced in male Fischer 344 rats by intratracheal instillation of pancreatic elastase (0.5 IU/g body weight). Four weeks after elastase instillation, animals were treated once daily, 4 days/week, for 3 weeks by exposing them nose-only to aerosolized ATRA (target concentration-time of 3000 or 15,000 mg-min/m3) or by injecting them intraperitoneally with ATRA in cottonseed oil (0.5 or 2.5 mg/kg). Based on estimates of particle deposition in the respiratory tract, inhalation doses were chosen to be consistent with injected doses. Lungs were fixed by inflation with formalin (constant pressure for 6 hours followed by >48 hours of immersion) and were embedded in paraffin. Sections were evaluated by histopathology and stereology. Inhalation exposure to ATRA at both aerosol concentrations caused significant elevations of ATRA in the lung, whereas only the high-dose injection treatment was associated with an elevation of lung ATRA. The mean ATRA concentration from lungs of rats in the high-dose inhalation exposure groups as measured by liquid chromatography--mass spectrometry was approximately 12-fold greater than that of high-dose injection-treated rats. Elastase instillation caused increased lung volumes, irregular alveolar air space enlargement, and fragmentation and attenuation of alveolar septa. Neither inhaled nor injected ATRA reduced the enlarged lung volumes associated with this emphysema model. Stereology demonstrated that alveolar air space enlargement in ATRA-treated rats was similar to that in sham-treated emphysematous animals. Thus, while inhalation treatment caused greater levels of the drug in lung tissue in comparison to that of injection-treated animals, treatment with ATRA by either route of administration did not cause a reversal of lung tissue damage in this model of elastase-induced emphysema.

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Elastase-induced changes in lung function: relationship to morphometry and effect of drugs

Cited by 30 publications

References 17 publications

Animal models of chronic obstructive pulmonary disease

Animal models of chronic obstructive pulmonary disease

A serine proteinase inhibitor isolated from Tamarindus indica seeds and its effects on the release of human neutrophil elastase

INHALATION ADMINISTRATION OF ALL-TRANS-RETINOIC ACID FOR TREATMENT OF ELASTASE-INDUCED PULMONARY EMPHYSEMA IN FISCHER 344 RATS

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