Emphysema model

Meng Q, Waters KM, Malard JM, Lee KM, Pounds JG. Gene expression modifications in a mouse emphysema model induced by elastase. Society of Toxicology, 2005. 

Several CMK inactivators have been examined in vivo. The relatively weak CMK (5-3) was tested in an elastase-induced emphysema model in the hamster. It was effective when administered i.p. at a total dose of 19 mg/hamster both before and after elastase exposme [113]. CMK (5-5) was effective i.t. at a dose of 0.5 mg/hamster when administered either 1 h before or 1 h after HLE exposure, in an identical model [114]. The most effective compound (5-6) worked following p.o. administration in a similar model in mice [115], or after i.t. administration in the elastase-induced acute haemorrhage model in hamsters [116]. Although peptide CMKs were the first low-molecular-weight inhibitors shown to be effective in vivo against elastase, they have consistently demonstrated toxic side-effects which have precluded their development [117, 118]. 

K. H. (1976a) Copper-deficient rat lung as an emphysema model. Fed. Proc. 35 255. 

Human leukocyte elastase is a protease that degrades elastin and other connective tissue components. It is implicated in the pathogenesis of pulmonary emphysema and other inflammatory diseases such as rheumatoid arthritis and cystic fibrosis. Porcine pancreatic elastase has often been used as a model for HLE. Both enzymes have a small primary binding site Si. 

Figure 13.10 TFMK inhibitors with sustained action in the hamster model of emphysema (Suckling, 1990).

Figure 1 The relative 6-year mortality hazard ratios are shown for reported usual sleep hr from 2-3 hr/night to 10 or more hr/night, relative to 1.0 assigned to the hazard for 7 hr/night as the reference standard. The solid line with 95% confidence interval bars shows results from a 32-covariate Cox proportional hazards survival model, as reported previously (3). The dotted lines show data from models that excluded subjects who were not initially healthy, i.e., who died within the first year or whose questionnaires reported any cancer, heart disease, stroke, chronic bronchitis, emphysema, asthma, or current illness (a yes answer to the question are you sick at the present time ). The dot-dash lines with X symbols show models controlling only for age, insomnia, and use of sleeping pills. Data were from 635,317 women and 478,619 men. The thin solid lines with diamonds show the percent of subjects with each reported sleep duration (right axis).

Addition of a low-molecular-weight substrate to the equilibrium mixture formed from equimolar amounts of SLPI and HLE resulted in time-dependent release of product, indicating that enzyme, inhibitor, substrate and their complexes were in true equilibrium [51]. Incubation of rSLPI-HLE complex with a,-PI resulted in dissociation of rSLPI and formation of an a,-PI-HLE complex. The fact that the dissociated rSLPI retained its ability to inhibit HLE is further indication that it may be a standard mechanism of action inhibitor [82]. In vivo, intratracheally instilled rSLPI is capable of significantly protecting against HLE-induced emphysema in the hamster (EMP model) for pretreatment times of up to 8 h [82]. 

Demonstration of in vivo activity by the saccharins was illustrated with (15-2) which was examined in the EMP model in hamster. It showed dose-related inhibition of PPE-induced emphysema when given i.t. (0.03-1.0 mg/ animal) 15 min. prior to PPE (0.1 mg /animal) insult. On a comparative weight basis it was consistently more potent than a,-PI [209]. 

AlAT) has been used in injectable form for the treatment of hereditary AlAT deficiency that markedly increases the risk of development of emphysema. Absorption of aerosolized human plasma and recombinant AlAT into the lymph and blood was studied in sheep and humans. Human plasma AlAT was found in the sheep blood and interstitial lymph at concentrations 1/1000 of that in the alveolar epithelial lining fluid (ELF). The recombinant human AlAT is non-glycosylated and has a terminal methionine residue. In the sheep model, this molecule disappears from the alveolar fluid faster than the human plasma AlAT, with the lymph levels around 10% of ELF and blood levels about 10% of the lymph. The recombinant form... 

Here again we have the problem of extrapolation but at least from a whole animal. In the whole animal, as in man, the multiple processes of metabolic activation and inactivation, and cellular interactions can occur and result in observable disease which is not the case in isolated cells. Therefore, why have we not been very successful in these types of studies Firstly, only a few life-time inhalation studies have been completed. Secondly, there has been only a limited success in developing animal models for human diseases, pulmonary and otherwise. We are interested in those diseases which are most likely to be associated with the inhalation of incompletely combusted plant and/or animal material. These diseases include lung cancer, emphysema, chronic bronchitis and cardiovascular disease. 

Pulmonary emphysema is a chronic progressive disorder wherein the elastic fibers of the lung become fragmented and dysfunctional with the result of a loss of elastic recoil. One result is that the patient must consciously and forcibly exhale. A prominent proposal for the etiology of the disease has been the lack of proteinase inhibitors that would otherwise prevent proteolytic degradation of the fiber.To help study the disease, a successful animal model for pulmonary emphysema was developed in which direct instillation of the proteolytic enzyme elastase into the lung became the causative agent. ° ... 

Experiments on rat and mice models of emphysema have shown that ATRA inhibited progression of airway obstruction [89] and promoted lung regeneration after injury [67]. Retinoic acid reduced the damage induced by elastase to cultured airway epithelial cells (ceU lines and primary cultures) [90]. 

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