Pulmonary model

Assessment of Pulmonary Targeting in Animal Models. Animal models are important tools in assessing the pharmacodynamic performance of antiasthma drugs. Pulmonary models have been developed for rat and mice, which allow the assessment of anti-inflammatory properties of a drug after antigen challenge. Alternatively, pulmonary eosinophilia can be induced by nonallergic modes,... 

The first SRS-A antagonist, FPL-55712 (26) (149), was discovered before the stmctures of the leukotrienes were detemiined. Although this compound is relatively weak as an antagonist and suffers from a very short half-life in vivo, it played an important role both in leukotriene stmcture elucidation and as a model for later antagonists. In work stmcturaHy related to FPL-55712, LY-171883 was developed (27) (150). LY-171883 was evaluated in several clinical trials before development was stopped. Orally adrninistered, LY-171883 blocked slightly the response to aerosol LTD improved pulmonary function (FEV ) in mild asthmatics (151), decreased the sensitivity of asthmatics to cold air-induced bronchoconstriction (152), and significantly reduced the bronchoconstrictor response to inhaled antigen (153). However, in all these studies the beneficial effects were minimal. 

PBPK models have also been used to explain the rate of excretion of inhaled trichloroethylene and its major metabolites (Bogen 1988 Fisher et al. 1989, 1990, 1991 Ikeda et al. 1972 Ramsey and Anderson 1984 Sato et al. 1977). One model was based on the results of trichloroethylene inhalation studies using volunteers who inhaled 100 ppm trichloroethylene for 4 horns (Sato et al. 1977). The model used first-order kinetics to describe the major metabolic pathways for trichloroethylene in vessel-rich tissues (brain, liver, kidney), low perfused muscle tissue, and poorly perfused fat tissue and assumed that the compartments were at equilibrium. A value of 104 L/hour for whole-body metabolic clearance of trichloroethylene was predicted. Another PBPK model was developed to fit human metabolism data to urinary metabolites measured in chronically exposed workers (Bogen 1988). This model assumed that pulmonary uptake is continuous, so that the alveolar concentration is in equilibrium with that in the blood and all tissue compartments, and was an expansion of a model developed to predict the behavior of styrene (another volatile organic compound) in four tissue groups (Ramsey and Andersen 1984). 

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. 

McKinley L, Kim J, Bolgos GL, Siddiqui J, Remick DG. CXC chemokines modulate IgE secretion and pulmonary inflammation in a model of allergic asthma. Cytokine 2005 32(3-4) 178-185. 

Findings from studies of schistosomiasis-induced liver fibrosis, as well as other models of pulmonary, kidney, and liver fibrosis, strongly support the role of CD4+ Th2 cells in the progression of fibrosis (4). In this regard, analyses of gene and protein expression after stimulation by Thl (vs. Th2) cytokines indicates that IL-4 is found at increased concentrations in the bronchoalveolar lavage (BAL) fluid of patients with idiopathic pulmonary fibrosis, as well as in the peripheral blood mononuclear cells of those afflicted with periportal fibrosis (10,53-56). 

Chemokines and Chemokine Receptors in Animal Models of Pulmonary Fibrosis... 

Chua F, Gauldie J, Laurent GJ. Pulmonary fibrosis searching for model answers. Am J Respir Cell Mol Biol 2005 33(1) 9-13. 

Hogaboam CM, Bone-Larson CL, Lipinski S, et al. Differential monocyte chemoattractant protein-1 and chemokine receptor 2 expression by murine lung fibroblasts derived from Thl- and Th2-type pulmonary granuloma models. J Immunol 1999 163(4) 2193-2201. 

Mercer, R.R. et al. (2008) Alteration of deposition pattern and pulmonary response as a result of improved dispersion of aspirated single-walled carbon nanotubes in a mouse model. American Journal of Physiology Lung Cellular and Molecular Physiology, 294 (1), L87-L97. 

Fig. 2a. Pulmonary and lymph node burdens of inhaled radioactive particles for Class W and Class Y compounds (no radioactive decay) as projected from the TGLD clearance model.

Fig. 4. Simplified rearrangement of the pulmonary clearance features of the kinetic model for retention and organ distribution of inhaled mCe.

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