Prostaglandins are lipid autacoids derived from arachidonic acid. They both sustain homeostatic functions and mediate pathogenic mechanisms, including the inflammatory response. They are generated from arachidonate by the action of cyclooxygenase isoenzymes, and their biosynthesis is blocked by nonsteroidal antiinflammatory drugs, including those selective for inhibition of cyclooxygenase-2. Despite the clinical efficacy of nonsteroidal antiinflammatory drugs, prostaglandins may function in both the promotion and resolution of inflammation. This review summarizes insights into the mechanisms of prostaglandin generation and the roles of individual mediators and their receptors in modulating the inflammatory response. Prostaglandin biology has potential clinical relevance for atherosclerosis, the response to vascular injury and aortic aneurysm.

Prostaglandins and Inflammation

Nonsteroidal anti-inflammatory drugs (NSAIDs) represent one of the most highly utilized classes of pharmaceutical agents in medicine. All NSAIDs act through inhibiting prostaglandin synthesis, a catalytic activity possessed by two distinct cyclooxygenase (COX) isozymes encoded by separate genes. The discovery of COX-2 launched a new era in NSAID pharmacology, resulting in the synthesis, marketing, and widespread use of COX-2 selective drugs. These pharmaceutical agents have quickly become established as important therapeutic medications with potentially fewer side effects than traditional NSAIDs. Additionally, characterization of the two COX isozymes is allowing the discrimination of the roles each play in physiological processes such as homeostatic maintenance of the gastrointestinal tract, renal function, blood clotting, embryonic implantation, parturition, pain, and fever. Of particular importance has been the investigation of COX-1 and -2 isozymic functions in cancer, dysregulation of inflammation, and Alzheimer's disease. More recently, additional heterogeneity in COX-related proteins has been described, with the finding of variants of COX-1 and COX-2 enzymes. These variants may function in tissue-specific physiological and pathophysiological processes and may represent important new targets for drug therapy.

Cyclooxygenase Isozymes: The Biology of Prostaglandin Synthesis and Inhibition

Maintaining research and development (R&D) productivity at a sustainable level is one of the main challenges currently facing the pharmaceutical industry. In this article, we discuss the results of a comprehensive longitudinal review of AstraZeneca's small-molecule drug projects from 2005 to 2010. The analysis allowed us to establish a framework based on the five most important technical determinants of project success and pipeline quality, which we describe as the five 'R's: the right target, the right patient, the right tissue, the right safety and the right commercial potential. A sixth factor - the right culture - is also crucial in encouraging effective decision-making based on these technical determinants. AstraZeneca is currently applying this framework to guide its R&D teams, and although it is too early to demonstrate whether this has improved the company's R&D productivity, we present our data and analysis here in the hope that it may assist the industry overall in addressing this key challenge.

Lessons learned from the fate of AstraZeneca's drug pipeline: a five-dimensional framework

Prostaglandin E Receptors

Prostaglandin (PG)D2, which has long been implicated in allergic diseases, is currently considered to elicit its biological actions through the DP receptor (DP). Involvement of DP in the formation of allergic asthma was recently demonstrated with DP-deficient mice. However, proinflammatory functions of PGD2 cannot be explained by DP alone. We show here that a seven-transmembrane receptor, CRTH2, which is preferentially expressed in T helper type 2 (Th2) cells, eosinophils, and basophils in humans, serves as the novel receptor for PGD2. In response to PGD2, CRTH2 induces intracellular Ca2+ mobilization and chemotaxis in Th2 cells in a Gαi-dependent manner. In addition, CRTH2, but not DP, mediates PGD2-dependent cell migration of blood eosinophils and basophils. Thus, PGD2 is likely involved in multiple aspects of allergic inflammation through its dual receptor systems, DP and CRTH2.

/pdf/prostaglandin-d2-selectively-induces-chemotaxis-in-t-helper-8nxev17qc2.pdf

Prostaglandin D2 Selectively Induces Chemotaxis in T Helper Type 2 Cells, Eosinophils, and Basophils via Seven-Transmembrane Receptor Crth2

Production of IgE caused by repeated topical application of 2,4-dinitrofluorobenzene (DNFB) to the ears of BALB/c mice was investigated. Ear thickness increased in proportion to the number of applications. Eczematous changes of the skin included marked infiltration of neutrophils, eosinophils, and monocytes and hypertrophy of the epidermis. Ear thickness due to inflammation reached a maximum 24 hours after the second, third, fourth, and fifth applications. The strong expression of interferon-gamma and IL-2 messenger RNA (mRNA) in the skin lesions indicated the participation of Th1 type helper T cells in the delayed-type hypersensitivity reaction. After the fifth application, the mice showed an immediate cutaneous reaction in addition to the delayed-type hypersensitivity reaction. The immediate reaction appeared within 1 hour of application. Hapten-specific IgE also was detected in serum from the mice, and the expression of germline and productive Cepsilon mRNA was detected in cervical lymph nodes, whereas productive Cepsilon mRNA was detected in the spleen. These results indicate that five topical applications of DNFB to the ear produce local eczematous dermatitis and increase serum hapten-specific IgE level in mice. Eczematous dermatitis is mainly caused by Th1 type T cells, and IgE production is mediated by Th2 type T cells in the cervical lymph nodes. In addition, IgE class switching occurs in the cervical nodes and IgE production occurs in both lymph nodes and spleen.

Immunoglobulin E Production in Mice by Means of Contact Sensitization with a Simple Chemical, Hapten.

FK-506 and Cyclosporin A Potentiate the IgE Antibody Production by Contact Sensitization with Hapten in Mice.

To study the role of interleukin (IL)‐4 in the onset of contact hypersensitivity (CH) in mice, the effect of IL‐4 gene‐depletion and anti‐IL‐4 monoclonal antibody treatment on dinitrofluorobenzene (DNFB)‐induced CH was examined. Simultaneously, to clarify the effect of background gene, DNFB‐induced CH in BALB/c and C57BL/6 mice was compared. Five repeated topical applications of DNFB to the ears of mice resulted in CH of the ears in terms of increases in ear thickness and histopathological changes. The magnitude of ear thickness increase in BALB/c mice was almost three times greater than that in C57BL/6 mice. The CH in BALB/c mice was significantly suppressed by IL‐4 gene‐depletion and anti‐IL‐4 monoclonal antibody treatment. In contrast, the symptoms of dermatitis in C57BL/6 mice were slightly affected by the same treatment. These changes corresponded well to the production of specific IgE antibody. Total IgE antibody production and the expression of productive Cε mRNA were dramatically suppressed by IL‐4 gene‐depletion and anti‐IL‐4 treatment in BALB/c and C57BL/6 mice. Neither total IgG nor IgM levels in either strain of mice was altered by depletion of IL‐4. The expression of IFN‐γ in the skin lesion was dramatically suppressed by IL‐4 gene‐depletion in BALB/c mice, but not in C57BL/6 mice. These findings indicate that IL‐4 plays an important role in the onset of DNFB‐induced CH in BALB/c mice, but not in C57BL/6 mice.

Different Role of IL-4 in the Onset of Hapten-induced Contact Hypersensitivity in BALB/c and C57BL/6 Mice.

The effect of overproduction of interleukin (IL) 5 on the allergic cutaneous response was investigated in transgenic mice overexpressing IL-5. Five repeated topical applications of 2, 4-dinitrofluorobenzene (DNFB) to the ears of mice resulted in allergic dermatitis on the ears as well as significant elevation in dinitrophenol-specific IgE antibody and total IgE in the serum in both wild-type and transgenic mice. The development of dermatitis as measured by skin thickness and histopathological changes were potentiated in the transgenic mice. In IL-5 transgenic mice, significant accumulation of eosinophils in skin lesions was observed after five paintings of DNFB, and the magnitudes of eosinophilia and IL-5 messenger RNA expression were significantly higher than in wild-type mice. The dinitrophenol-specific and total IgE in the serum were higher in IL-5 transgenic mice. The late phase reaction of IgE antibody-mediated biphasic cutaneous response was potentiated in IL-5 transgenic mice. The magnitudes of vasopermeability increase by passive cutaneous anaphylaxis, serotonin, and platelet-activating factor were similar in both mice. These results indicate that overproduction of IL-5 resulted in the potentiation of DNFB-induced dermatitis by elevation of IgE production, IgE-mediated allergic late-phase cutaneous reaction, and eosinophilia in the skin lesion.

Effect of Overproduction of Interleukin 5 on Dinitrofluorobenzene-induced Allergic Cutaneous Response in Mice.

Interleukin-4 Is Involved in Allergen-induced Airway Eosinophilic Inflammation and Bronchial Hyperresponsiveness Independent of Genetic Background.

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