effect and its applicability to humans is not yet known. 20-hydroxyeicosatetraenoic acid (20-hete), a product of arachidonic acid formed by cytochrome p450 omega hydroxylases, and certain isoprostanes, which form by non-enzymatic free radical attack on arachidonic acid, constrict rodent and human artery preparations by directly activating tp. while significantly less potent than thromboxane a2 in activating this receptor, studies on rat and human cerebral artery preparations indicate that increased blood flow through these arteries triggers production of 20-hete which in turn binds tp receptors to constrict these vessels and thereby reduce their blood blow. acting in the latter capacity, 20-hete, it is proposed, functions as a txa2 analog to regulate blood flow to the brain and possibly other organs. isoprostanes form in tissues undergoing acute or chronic oxidative stress such as occurs at sites of inflammation and the arteries of diabetic patients. high levels of isoprostanes form in ischemic or otherwise injured blood vessels and acting through tp, can stimulate arterial inflammation and smooth muscle proliferation; this isoprostane-tp axis is proposed to contribute to the development of atherosclerosis and thereby heart attacks and strokes in humans. lung allergic reactivity tp receptor activation contracts bronchial smooth muscle preparations obtained from animal models as well as humans and contracts airways in animal models. in a mouse model of asthma (i.e. hypersensitivity to ovalabumin), a tp receptor antagonist decreased the number of eosinophils infiltrating lung as judged by their content in bronchoalveolar lavage fluid and in a mouse model of dust mite-induced astha, deletion of tbxa2r prevented the development of airways contraction and pulmonary eosinophilia responses to allergen. another tp receptor agonists likewise reduced airway bronchial reactivity to allergen as well as symptoms in volunteers with asthma. the tp receptor appears to play and essential role in the pro-asthmatic actions of leukotriene c4 (ltc4): in ovalbumin-sensitized mice, leukotriene c4 increased the number of eosinophils in bronchoalveolar lavage fluid and simultaneously decreased the percentages of eosinophils in blood but these responses did not occur in tbxa2r-deficient mice. ltc4 also stimulated lung expression of the pro-inflammatory intracellular adhesion molecules, icam-1 and vcam-1 by a tp receptor-dependent mechanism. these findings suggest that tp contributes to asthma in animal models at least in part by mediating the actions of ltc4. further studies are required to determine if tp receptor antagonists might be useful for treating asthma and other airway constriction syndromes such as chronic obstructive lung diseases in humans. uterus along with pgf2α acting through its fp receptor, txa2 acting through tp contracts uterine smooth muscle preparations from rodents and humans. since the human uterus loses its sensitivity to pgp2α but not to txa2 during the early stages of labor in vaginal childbirth, tp agonists, it is suggested, might be useful for treating preterm labor failures. immune system activation of tp receptors stimulates vascular endothelial cell pro-inflammatory responses such as increased expression of cell surface adhesion proteins (i.e. icam-1, vcam-1, and e-selectin); stimulates apoptosis (i.e. cell death) of cd4+ and cd8+ lymphocytes; causes the chemokinesis (i.e. cell movement) of native t cells; and impairs the adhesion of dendritic cells to t cells thereby inhibiting dendritic cell-dependent proliferation of t cells. tp deficient mice exhibit an enhanced contact hypersensitivity response to dnfb thymocytes in the thymus of these deficient mice are resistant to lipopolysaccharide-induced apoptosis. tp receptor-depleted mice also gradually develop with age extensive lymphadenopathy and, associated with this, increased immune responses to foreign antigens. these studies indicate that txa2-tp signaling functions as a negative regulator of dc-t cell interactions and possibly thereby the acquisition of acquired immunity in mice. further studies are needed to translate these mouse studies to humans. cancer increased expression of cyclooxygenases and their potential involvement in the progression of various human cancers have been described. some studies suggest that the txa2 downstream metabolite of these cyclooxygenases along with its tp receptor contribute to mediating this progression. tp activation stimulates tumor cell proliferation, migration, neovascularization, invasiveness, and metastasis in animal models, animal and human cell models, and/or human tissue samples in cancers of the prostate, breast, lung, colon, brain, and bladder. these findings, while suggestive, need translational studies to determine their relevancy to the cited human cancers. clinical significance isolated cases of humans with mild to moderate bleeding tendencies have been found to have mutations in tp that are associated with defects in this receptors binding of txa2 analogs, activating cell signal pathways, and/or platelet functional responses not only to tp agonists but also to agents that stimulate platelets by tp-independent mechanisms (see genomics section below). drugs in use targeting tp tp receptor antagonist seratrodast is marketed in japan and china for the treatment of asthma. picotamide, a dual inhibitor of tp and txa2 synthesis, is licensed in italy for the treatment of clinical arterial thrombosis and peripheral artery disease. these drugs are not yet licensed for use in other countries. clinical trials while functional roles for tp receptor signaling in diverse homeostatic and pathological processes have been demonstrated in animal models, in humans these roles have been demonstrated mainly with respect to platelet function, blood clotting, and hemostasis. tp has also been proposed to be involved in human: blood pressure and organ blood flow regulation; essential and pregnancy-induced hypertension; vascular complications due to sickle cell anemia; other cardiovascular diseases including heart attack, stroke, and peripheral artery diseases; uterine contraction in childbirth; and modulation of innate and adaptive immune responses including those contributing to various allergic and inflammatory diseases of the intestine, lung, and kidney. however, many of the animal model and tissue studies supporting these suggested functions have yet to be proven directly applicable to human diseases. studies to supply these proofs rest primarily on determining if tp receptor antagonists are clinically useful. however, these studies face issues that drugs which indirectly target tp (e.g. nonsteroidal anti-inflammatory drugs that block txa2 production) or which circumvent tp (e.g. p2y12 antagonists that inhibit platelet activation and corticosteroids and cysteinyl leukotriene receptor 1 antagonists that suppress allergic and/or inflammatory reactions) are effective treatments for many putatively tp-dependent diseases. these drugs are likely to be cheaper and may prove to have more severe side effects that tp-targeting drugs. these considerations may help to explain why relatively few studies have examined the clinical usefulness of tp-targeting drugs. the following translation studies on tp antagonists have been conducted or are underway: in a non-randomized, uncontrolled examination, 4 weeks of treatment with tp receptor antagonist aa-2414 significantly reduced bronchial reactivity in asthmatic patients. a follow-up double-blind placebo controlled study of asthmatic patients found that tp receptor antagonist seratrodast significantly reduced airway flow (i.e. fev1), diurnal variation in fev1, airway responsiveness to contractive stimulation, airway inflammation, and airway content of pro-allergic mediators (i.e. rantes, ccl3, ccl7, and eotaxin). a phase 3 study, tp antagonist terutroban was tested against aspirin as a preventative of recurrent as well as new ischemia events in patients with recent strokes or transient ischemic attacks. the study did not meet its primary end points compared to aspirin-treated controls and was stopped; patients on the drug experienced significant increases in minor bleeding episodes. a study comparing the safety and efficacy of tp antagonist ridogrel to aspirin as adjunctive therapy in the emergent treatment of heart attack with the clot dissolving agent streptokinase found that ridogrel gave no significant enhancement of clot resolution but was associated with a lower incidence of recurrent heart attack, recurrent angina, and new strokes without causing excess bleeding **complications. tp antagonist ifetroban is in phase 2 clinical development for the treatment of kidney failure. in addition to the above tp antagonists, drugs that have dual inhibitory actions in that they block not only tp but also block the enzyme responsible for making txa22, thromboxane-a synthase, are in clinical development. these dual inhibitor studies include: a long-term study in diabetic patients compared dual inhibitor picotamide to aspirin for improving ischemia symptoms caused be peripheral artery diseases found not difference in primary end points but also found that picotamide therapy significantly reduced cardiovascular mortality over a 2-year trial. a phase 2 clinical trial of dual inhibitor terbogrel to treat vasoconstriction was discontinued due to its induction of leg pain. dual inhibitor ev-077 is in clinical phase ii development. genomics several isolated and/or inherited cases of patients suffering a mild to moderately severe bleeding diathesis have been found to be associated with mutations in 'the 'tbxa2r gene that lead to abnormalities in the expression, subcellular location, or function of its tp product. these cases include: a missense mutation causing tryptophan (trp) to be replaced by cysteine (cys) as its 29th amino acid (i.e. trp29cys) yields a tp which is less responsive to stimulation by a tp agonist, less able to activate its gq g protein target, and poorly expressed at the cell's surface. some or perhaps all of these faults may reflect the failure of this mutated tp to form tp-tp dimers. an asn42ser mutation yields a tp that remains in the cell's golgi apparatus and fails to be expressed at the cell surface. an asp304asn mutation yields a tp that exhibits decreased binding and responsiveness to a tp agonist. an arg60leu mutation yields a tp that is normally expressed and normally binds a tp agonist but fails to activate its gq g protein target. a missense mutation that replaces thymine (t) with guanine (g) as the 175 nucleotide (c.175c>t) in the tbxa2r gene as well as cc87g>c and c.125a>g mutations yield tp's that are poorly expressed. a c.190g>a mutation yields a tp that binds a tp agonist poorly. a guanine (g) duplication at the 167th nucleotide causes a frameshift mutation (c.165dupg) at amino acid #58 to yield a poorly expressed tp mutant. single nucleotide polymorphism (snp) variations in the tbxa2r gene have been associated with allergic and cardiovascular diseases; these include: meta-analysis of several studies done on different population test groups has confirmed an association of tbxa2r single nucleotide polymorphism (snp) variant 924c>t with an increased risk of developing asthma. the frequency of snp 795t>c variant in tbxa2r was found in separate studies of south korean and japanese test groups and the frequency of the snp variant -6484c>t preceding the tbxa2r gene in a study of a south korean test group was found to be elevated in patients suffering a type of severe asthma termed aspirin-induced asthma. both 795t>c and 924c>t snp variants encode a tp receptor that exhibits increased binding and responsiveness to txa2 analogs. snp variant -4684t was associated with reduced gene promoter activity in the tbxa2r gene and an increased incidence of developing aspirin-induced urticarial in a korean test group. snp variant rs768963 in tbx2r was associated with increased frequency of large artery atherosclerosis, small artery occlusion, and stroke in two separate studies of chinese test groups. in one of the latter groups, the t-t-g-t haplotype of c795t-t924c-g1686a-rs768963 was significantly less frequent in patients suffering stroke. snp variant rs13306046 exhibited a reduction in microrna-induced repression of tbxa2r gene expression and was associated with decreased blood pressure in a scandinavian caucasian test group.