Prostaglandins which have

The cell damage associated with inflammation acts on cell membranes to cause leukocytes to release lysosomal enzymes arachidonic acid is then liberated from precursor compounds, and various eicosanoids are synthesized. As discussed in Chapter 18, the cyclooxygenase (COX) pathway of arachidonate metabolism produces prostaglandins, which have a variety of effects on blood vessels, on nerve endings, and on cells involved in inflammation. The lipoxygenase pathway of arachidonate metabolism yields leukotrienes, which have a powerful chemotactic effect on eosinophils, neutrophils, and macrophages and promote bronchoconstriction and alterations in vascular permeability. 

Fig. 35.7. The thromboxane ring. In contrast to the prostaglandins, which have a five-mem-bered carbon ring, thromboxanes have a six-membered ring (shown in blue) containing an oxygen atom. Substituents are attached to the ring at carbons 9 and 11. In the case of TXA2 (shown above), an oxygen atom connects carbons 9 and 11.

The synthesis of prostaglandin and thromboxane hormones by cyclooxygenase enzymes is another important target of NO. With the exception of red blood cells, all mammalian cells release prostaglandins, which have an important role in inflammatory response, formation of blood clots, regulation of blood pressure, and muscle contraction. 

Included among other differentiating cell lines which have been established in culture, is the human promyelocytic cell line HL-60, which differentiates into more mature myeloid cells upon treatment with retinoic acid and prostaglandin E] (PGEi). Friend erythroleukemia cells differentiate into hemoglobin-producing cells when treated with either dimethyl sulfoxide, or hexamethylene bis-acetamide. 

Although infection with C. parvum is considered predominantly secretory, histopathologic studies have revealed varying degrees of villous atrophy and infiltration of inflammatory cells beneath the epithelial mucosa [85, 86], Prostaglandins, which are known to induce cAMP-mediated apical chloride secretion and inhibit electroneutral sodium chloride and water absorption in enterocytes, have been demonstrated to be elevated in a porcine model of cryptosporidiosis [87], Inflammatory cytokines such as IL-1, IL-8 and TNF-a are induced in intestinal epithelial cell lines infected with Cryptosporidium and in animal models of cryptosporidiosis and have been postulated to play a role in pathogenesis [88, 89], Expression of TNF-a and IL-1 mRNA in the majority of jejunal biopsies of adult volunteers after experimental infection were also observed, although this did not correlate with the enteric symptoms [90]. 

In sensitized asthmatic individuals, antigen challenge generally causes a Type I (IgE-mediated) immediate hypersensitivity response by release of preformed mediators, including histamine, and prostaglandins, which are responsible for bronchoconstric-tion and increased vascular permeability. Between 2 and 8 hours after the immediate response, asthmatics experience a more severe and prolonged (late phase) reaction that is characterized by mucus hyper-secretion, bronchoconstriction, airway hyperresponsiveness to a variety of nonspecific stimuli (e.g., histamine, methacholine), and airway inflammation characterized by eosinophils. This later response is driven by leukotrienes, chemokines and cytokines synthesized by activated mast cells and Th2 cells. Both proteins and haptens have been associated with these types of reactions. 

Arachidonic acid (C20 4 n-6) is the precursor for the synthesis of prostaglandin molecules (Section 4.4.4), which have a wide range of biochemical effects on for example, the perception of pain, inflammation, blood clotting and smooth muscle contraction. Docosahexaenoic acid (DHA, C22 6) and eicosapentaenoic acid (EPA, C20 5) are both n-3 long-chain polyunsaturated fatty acids (PUFA) which have been shown to have significantly beneficial effects on intellectual development and inflammatory conditions such as asthma and cardiovascular disease. 

Recent work in the early 2000s showed a more complicated role for the COX-2 enzyme together with additional enzymes, COX-2 generates a number of other prostaglandin compounds besides PGE2, which have other regulatory functions ... 

The bisphosphonates are all analogues of pyrophosphate. They inhibit osteoclast resorption of bone and they are able to inhibit the formation and dissolution of hydroxyapatite crystals, however their exact mechanism is not well understood. Other effects which have relevance for bone homeostasis include inhibition of the activities of PTH, prostaglandins and 1,25-dihydroxy vitamin D. Bisphosphonates bind to bone with high affinity. They have therefore a duration of action that continues long after their use has been stopped. 

Most drugs are administered to infants and children for the same therapeutic indications as for adults. However, a few drugs have found unique uses in children. Among these are theophylline and caffeine, which are used to treat apnea of prematurity indomethacin, which closes a patent ductus arteriosus and prostaglandin Ej, which maintains the patency of the ductus arteriosus. Paradoxically, drugs such as phenobarbital, which have a sedating action on adults, may produce hyperactivity in children, and some adult stimulant drugs, such as methyl-phenidate, are used to treat children with hyperactivity. 

Carboxylic acids, compounds of the type RCOH, constitute one of the most frequently encountered classes of organic compounds. Countless natural products are carboxylic acids or are derived from them. Some carboxylic acids, such as acetic acid, have been known for centuries. Others, such as the prostaglandins, which are powerful regulators of numerous biological processes, remained unknown until relatively recently. Still others, aspirin for example, are the products of chemical synthesis. The therapeutic effects of aspirin, welcomed long before the discovery of prostaglandins, are now understood to result from aspirin s ability to inhibit the biosynthesis of prostaglandins. 

Mammals lack the enzymes to insert double bonds at carbon atoms beyond C-9 in the fatty acid chain. Thus they cannot synthesize linoleate and linole-nate, both of which have double bonds later in the chain than C-9 (linoleate has cis, cis A9, A12 double bonds, and linolenate has all-ris A9, A12, A15 double bonds). Hence, in mammals linoleate and linolenate are called essential fatty acids since they have to be supplied in the diet. These two unsaturated fatty acids are also the starting points for the synthesis of other unsaturated fatty acids, such as arachidonate. This C20 4 fatty acid is the precursor of several biologically important molecules, including the prostaglandins, prostacyclins, thromboxanes and leukotrienes (see Topic Kl). 

---