Gastrointestinal tract vascular permeability

The human histamine Hi-receptor is a 487 amino acid protein that is widely distributed within the body. Histamine potently stimulates smooth muscle contraction via Hi-receptors in blood vessels, airways and in the gastrointestinal tract. In vascular endothelial cells, Hi-receptor activation increases vascular permeability and the synthesis and release of prostacyclin, plateletactivating factor, Von Willebrand factor and nitric oxide thus causing inflammation and the characteristic wheal response observed in the skin. Circulating histamine in the bloodstream (from, e.g. exposure to antigens or allergens) can, via the Hi-receptor, release sufficient nitric oxide from endothelial cells to cause a profound vasodilatation and drop in blood pressure (septic and anaphylactic shock). Activation of... 

The underlying dermis is more permeable and vascularized, but to reach the systemic circulation through the skin, the toxic compound would have to traverse several layers of cells, in contrast to the situation in, for example, the gastrointestinal tract, where only two cells may separate the compound from the bloodstream. 

There are three main sites of absorption skin (large surface area poorly vascularized not readily permeable) gastrointestinal tract (major site well vascularized variable pH large surface area transport processes food gut bacteria) lungs (very large surface area well vascularized readily permeable). Compounds may be administered by direct injection (i.p., i.m., s.c., i.v.). 

Clostridium perfringens has at least six serotypes and produces over 20 toxins. Epsilon toxin, along with alpha, beta, and iota toxins, is dermonecrotic and lethal. It is produced by some strains of type B and especially type D as a protoxin that is then converted to an active, mature, heat-labile toxin. The resulting toxin binds to cell membranes and forms a membrane complex that promotes the efflux of intracellular potassium. Because the usual route of entry is the gastrointestinal tract, the resulting pathology is an increase in intestinal permeability that enhances absorption of more toxin and ensures systemic toxemia. In animals, increased vascular permeability leads to enterotoxemia, pulpy kidney , altered hepatic function, and cerebral edema and necrosis. 

Histamine plays a central role in immunologic and anti-inflammatory responses, particularly in the immediate hypersensitivity response. Three subclasses of histamine receptors have been identified Hj, Hj, and Hj receptors. Hj receptors are involved in mediating increased vascular permeability, pruritus, coutraction of smooth muscle in the respiratory and gastrointestinal tracts, release of mediators of inflammation, and recruitment of inflammatory cells. Among other effects, Hj receptors mediate the negative feedback control of histamine synthesis and release and may play some defensive role against excess bronchoconstriction. H, and Hj receptors are both found primarily in bronchial smooth muscle in the human respiratory tract (40). 

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