A physiological examination of mice harboring a null allele at the aryl hydrocarbon (Ah) locus revealed that the encoded aryl hydrocarbon receptor plays a role in the resolution of fetal vascular structures during development. Although the aryl hydrocarbon receptor is more commonly studied for its role in regulating xenobiotic metabolism and dioxin toxicity, a developmental role of this protein is supported by the observation that Ah null mice display smaller livers, reduced fecundity, and decreased body weights. Upon investigating the liver phenotype, we found that the decrease in liver size is directly related to a reduction in hepatocyte size. We also found that smaller hepatocyte size is the result of massive portosystemic shunting in null animals. Colloidal carbon uptake and microsphere perfusion studies indicated that 56% of portal blood flow bypasses the liver sinusoids. Latex corrosion casts and angiography demonstrated that shunting is consistent with the existence of a patent ductus venosus in adult animals. Importantly, fetal vascular structures were also observed at other sites. Intravital microscopy demonstrated an immature sinusoidal architecture in the liver and persistent hyaloid arteries in the eyes of adult Ah null mice, whereas corrosion casting experiments described aberrations in kidney vascular patterns.T he aryl hydrocarbon receptor (AHR) is a member of the per-arnt-sim (PAS) superfamily of proteins. The AHR regulates biological responses to a variety of environmental contaminants, such as the polycyclic aromatic hydrocarbons found in cigarette smoke, the polychlorinated dioxins that contaminate industrial chemicals, and the wartime defoliant Agent Orange (1-5). These chemical ligands bind to the AHR, leading to receptor dimerization with another PAS protein known as the aryl hydrocarbon nuclear translocator (ARNT). This heterocomplex interacts with genomic enhancer elements upstream of a battery of target genes that encode xenobiotic metabolizing enzymes (1, 6, 7). The observation that the up-regulated enzymes often have metabolic activity toward AHR agonists has led to the idea that this pathway represents an adaptive metabolic response that protects an organism from exposure to certain classes of toxic environmental contaminants. Although this adaptive role has considerable experimental support, this pathway is not always protective. Exposure to high-affinity AHR agonists, like the chlorinated dioxins, can result in cancer (8), immunosuppression (9), liver damage (10), and birth defects (11). The mechanisms underlying these toxic effects are unknown but appear to be AHR mediated.Because of its role in mediating responses to environmental contaminants, the biology of the AHR has been extensively characterized from a toxicological viewpoint. However, several observations suggest an additional role for the AHR in vertebrate development. First, a phylogenetic survey indicates that the AHR arose over 450 million years ago, with functional orthologs found in species that have evolved in vario...
Organ preservation is the supply line for organ transplantation. Currently, the liver, pancreas, and kidney can be successfully preserved for up to two days by flushing the organs with the University of Wisconsin (UW) organ preservation solution and storing them at hypothermia (0-5 degree C). The UW solution is effective because it uses a number of cell impermeant agents (lactobionic acid, raffinose, hydroxyethyl starch) that prevent the cells from swelling during cold ischemic storage. Additionally, the UW solution contains glutathione and adenosine, agents that may stimulate recovery of normal metabolism upon reperfusion by augmenting the antioxidant capacity of the organs (glutathione) or by stimulating high-energy phosphate generation (adenosine) upon reperfusion. Although this method of organ preservation is effective, some organs (5-15% of livers and 20-30% of kidneys) do not function well upon transplant. Injury may be preservation related but may also result from donor and recipient factors that render the organs more susceptible to preservation damage. Results with continuous perfusion of kidneys in the clinics show a reduction in preservation/reperfusion damage. This may be a more appropriate preservation method than cold storage. In this chapter we discuss the development and use of the UW solution and present clinical results. Although intraabdominal organs are well preserved at present, intrathoracic organs (lungs and heart) are less well preserved, and better methods for preservation of these organs are needed for increased use of lung and heart transplantation.
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