HHS Vulnerability Disclosure, Help 1b-e; Supplementary Fig. [10][47] Initially there was no clearly established definition, which resulted in controversy regarding the incidence and death of ARDS. Classical estrogen receptor alpha signaling mediates negative and positive feedback on gonadotropin-releasing hormone neuron firing. Rebouche CJ, Chenard CA. In spite of these disadvantages, trichome-based resistance derived from wild potatoes has generally proved to be a useful, broad-spectrum, and popular resistance source. The acute phase of inflammation is characterized by the rapid influx of blood granulocytes, typically neutrophils, followed swiftly by monocytes that mature into inflammatory macrophages that subsequently proliferate and thereby affect the functions of resident tissue macrophages. 17). Nagoshi H, Uehara Y, Kanai F, Maeda S, Ogura T, Goto A, Toyo-oka T, Esumi H, Shimizu T, Omata M. Prostaglandin D2 inhibits inducible nitric oxide synthase expression in rat vascular smooth muscle cells. Gutierrz-Alcal et al. An additional complication is that some alveoli can only be opened with higher airway pressures than are needed to keep them open, hence the justification for maneuvers where PEEP is increased to very high levels for seconds to minutes before dropping the PEEP to a lower level. One of the most widely used mechanisms for controlling estrogen synthesis in the body is regulation of the enzyme aromatase. History of aromatase: saga of an important biological mediator and therapeutic target. performed the statistical analysis and critical review of the manuscript. Osterlund MK, et al. Drs. Cotton fibers are another type of trichomes, characterized by polar elongation feature. 2f). Our unindicted coconspirators: human metabolism from a microbial perspective. performed the initial metabolomics study, assisted with animal and mass spectrometry analyses. Growth factors (GF) activate protein-kinase cascades, leading to phosphorylation (P) and activation of nuclear ERs at EREs. Liston TE, Roberts LJ., II Transformation of prostaglandin D2 to 9 alpha, 11 beta-(15S)-trihydroxyprosta- (5Z,13E)-dien-1-oic acid (9 alpha, 11 beta-prostaglandin F2): A unique biologically active prostaglandin produced enzymatically in vivo in humans. National Library of Medicine COX-2 prefers prostaglandin I synthase (PGIS) and the microsomal (m) PGES isozymes, both of which are often coinduced along with COX-2 by cytokines and tumor promoters (4). Taken together, these data show that gut-microbiota dependent metabolite TMAO fosters alterations in a major pathway for cholesterol elimination from the body, the bile acid synthetic pathway. The vessels carry a clear fluid called lymph (the Latin word lympha refers to the deity of fresh water, Previous studies demonstrate that transcription factors R2R3 MYB, WD40 repeat protein, basic helix-loop-helix protein, and C2H2 zinc finger protein, and some phytohormones regulate trichome development (Serna and Martin, 2006; Ishida etal., 2008; Yang and Ye, 2013; Wang and Chen, 2014). Pulichino AM, Rowland S, Wu T, Clark P, Xu D, Mathieu MC, Riendeau D, Audoly LP. Indeed, recent studies found that mice with ovariectomy or overexpression of ERE did not change the mechanic loading-induced upregulation of osteogenic activity. Also 15d-PGJ2, binds with low affinity the nuclear PPAR (110). The definition required the following criteria to be met: If PaO2:FiO2 < 300 mmHg (40 kPa), then the definitions recommended a classification as "acute lung injury" (ALI). TMA too has been reported to influence signal transduction by direct interaction with a family of G couple protein receptors48,49. 4). For example, deletion of the IP does not result in spontaneous thrombosis but rather accentuates the response to thrombogeneic stimuli. These ovary-derived estrogens are released into general circulation and target distal estrogen-responsive tissues including reproductive and non-reproductive organs. These results are consistent with a gut microbiota dependent mechanism whereby generation of TMAO impairs RCT, potentially contributing to the observed pro-atherosclerotic phenotype of these interventions. Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. In addition to the upregulation of macrophage scavenger receptors potentially contributing to enhanced forward cholesterol transport10, we show that TMAO, and its dietary precursors choline and carnitine, suppress reverse cholesterol transport through gut microbiota-dependent mechanisms in vivo. Dayer JM, Krane SM, Russell RG, Robinson DR. Production of collagenase and prostaglandins by isolated adherent rheumatoid synovial cells. Levin ER. Use of prostaglandin in cows with unobserved oestrus. Moriyama T, Higashi T, Togashi K, Iida T, Segi E, Sugimoto Y, Tominaga T, Narumiya S, Tominaga M. Sensitization of TRPV1 by EP1 and IP reveals peripheral nociceptive mechanism of prostaglandins. The platelet is a small, anucleated cell that originally derives from the hematopoietic lineage via the megakaryocyte. When compared to wild-type mice, the deficiency of COX-2 reduces the level of PGE2 production by approximately 75%, while the deficiency of COX-1 reduces the PGE2 level by 25% during this early stage. Generation and reproductive phenotypes of mice lacking estrogen receptor beta. 2013 Mar; 19(3): 197209. In addition to acting directly through EREs, ligand-activated nuclear ERs can regulate transcription by a nonclassical pathway through ER-DNA indirect association such as interacting with and influencing the activity of other transcription factors, such as stimulating protein-1 (SP-1), activator protein 1 (AP-1), nuclear factor B (NF-B), and c-jun [67]. This receptor is expressed in kidney, liver, lung, platelets, heart, and aorta (84). [21], Some practitioners favor airway pressure release ventilation when treating ARDS. 8). To date no studies have explored the participation of our commensal intestinal microbiota in modifying the diet-host interaction during consumption of red meat. Cyclooxygenases: Structural, cellular, and molecular biology. While the pro-inflammatory properties of individual prostaglandins during the acute inflammatory response are well established, their role in the resolution of inflammation is more controversial. For example, trichomes found in the axils of typically sheathing leaves, which may function in secreting protective mucilage, are termed intravaginal (or axillary) squamules (found, e.g., in many Alismatales). conceived the idea, helped design the experiments, provided the funding for the study, and helped draft and critically revised the manuscript. Transcriptional regulation of the human aromatase cytochrome P450 gene expression in human placental cells. S.L.H. Prostaglandin E(2)-EP4 signaling promotes immune inflammation through T(H)1 cell differentiation and T(H)17 cell expansion. 3b). Thon JN, Italiano JE., Jr Does size matter in platelet production? Increasing evidence that estrogen synthesis and signaling can be both tissue- and cell-specific suggests that estrogens are not simply female sex hormones for gonadal organ development and function. In both genders, epidemiological studies show an increased risk for AD with the age-related loss of sex steroid hormones. One pro-atherosclerotic mechanism observed for TMAO in the current studies is reduction of RCT (Fig. The generation of mPGES-1-deficient mice has revealed the dominant role of this enzyme in PGE2 generation relevant to promotion of inflammation. Studies showed that estrogen therapy plays osteoprotective roles in both osteoporotic humans and rodents [104], while whether estrogen therapy can protect against heart disease or AD remain controversial [105]. Aspergillus versicolor is a slow-growing filamentous fungus commonly found in damp indoor environments and on food products. Cloning of a novel receptor expressed in rat prostate and ovary. Selkoe DJ, et al. Carnitine deficiency disorders in children. mPGES-1 is a perinuclear protein that is markedly induced by cytokines and growth factors and downregulated by anti-inflammatory glucocorticoids as in the case of COX-2 (42, 43). Cellular mechanisms of estradiol-mediated sexual differentiation of the brain. The coding region spans nine exons (exon II-X), which are identical in all mRNA species and encode the same protein and 3'-UTR of the mRNA regardless of the tissue or the promoter used. L-carnitine is essential in the import of activated long chain fatty acids from the cytoplasm into mitochondria for -oxidation and supplementation with L-carnitine has been widely studied. From: Sustainable Management of Arthropod Pests of Tomato, 2018, Michael G. Simpson, in Plant Systematics (Third Edition), 2019. The high consumption of meat in the developed world is linked to cardiovascular disease (CVD) risk, presumably due to the large content of saturated fats and cholesterol found in meat 1,2.However, recent meta-analysis of prospective cohort studies showed no association between dietary saturated fat intake and CVD, prompting the suggestion that other 15-deoxy-delta 12,14-prostaglandin J2 inhibits multiple steps in the NF-kappa B signaling pathway. Estrogens can also decrease the level of hyperphosphorylated tau (a major component of neurofibrillary tangles) by modulating the kinases and phosphatases involved in tau phosphorylation, such as GSK-3, Wnt, or PKA pathways [142]. (a) Structure of carnitine and scheme of carnitine and choline metabolism to TMAO. Some of the beneficial effects of estrogen that protect the cardiovascular system are mediated through ER-dependent mechanisms. Follicular oestrogen synthesis: the `two-cell, two-gonadotrophin' model revisited. Cookie se pouv k uloen souhlasu uivatele s cookies v kategorii Vkon. Bocchinfuso WP, Korach KS. Both of these prostaglandins have G protein-coupled receptors (GPCRs) on the surface of the platelet that are selectively activated by their respective metabolites and play a role in reinforcing platelet activation. NSAIDs bind to and inactivate the COX site at only one of the monomers of the COX dimer and this is sufficient to shut down prostanoid formation (14). Additionally, TP can also be coupled via Gh to phospholipase C as well as via Gi and Gs to adenylate cyclase. ), and the Leducq Foundation (S.L.H.). PGE2, binding to different EP receptors, can regulate the function of many cell types including macrophages, dendritic cells and T and B lymphocytes leading to both pro- and anti-inflammatory effects. P.M. Bleeker, in Methods in Enzymology, 2016. Hierarchical organization in the hemostatic response and its relationship to the platelet-signaling network. This process causes the cardinal signs of acute inflammation: rubor (redness), calor (heat), tumor (swelling) and dolor (pain). The age-related expression of ER and ER has been studied in rodent cerebral cortex and the result showed that ER and ER undergo differential changes in expression during aging: ER level did not change with aging while ER level decreases signicantly with advancing age in both sexes [114]. The EP4 receptor also appears to play a pro-inflammatory role in the pathogenesis of rheumatoid arthritis. Chen D, et al. Elssner T, Preusser A, Wagner U, Kleber HP. Aromatase expression in health and disease. INTRODUCTION. Peltate trichomes are those with a disk-shaped apical portion atop a peltately attached stalk. Mice deficient in the EP4 but not in the EP1, EP2, or EP3 receptors exhibit an attenuated response in the collagen antibody induced arthritis model, with significantly lower levels of the inflammatory cytokines IL-6 and IL-1 and a dramatic reduction in the clinical signs of disease (61). In fact, the suspicion that the cholesterol and saturated fat content of red meat may not be sufficiently high to account for observed risks has stimulated investigation of alternative disease-promoting exposures that accompany dietary meat ingestion, such as high salt content, or heterocyclic compounds generated during cooking4,5. Novensa L, et al. It has a characteristic musty odor associated with moldy homes and is a major producer of the hepatotoxic and carcinogenic mycotoxin sterigmatocystin. Takahashi Y, Tokuoka S, Masuda T, Hirano Y, Nagao M, Tanaka H, Inagaki N, Narumiya S, Nagai H. Augmentation of allergic inflammation in prostanoid IP receptor deficient mice. [51][52], There is ongoing research on the treatment of ARDS by interferon (IFN) beta-1a to aid in preventing leakage of vascular beds. Cookie se pouv k uloen souhlasu uivatele s cookies v kategorii Jin". The https:// ensures that you are connecting to the [citation needed], Neutrophils and some T-lymphocytes quickly migrate into the inflamed lung tissue and contribute in the amplification of the phenomenon. Wu KK, Liou JY. Together, these findings illustrate that deletion or inhibition of mPGES- 1 markedly reduces inflammatory response, in several mouse models. The other monomer appears to play an allosteric function. Dr. Hazen reports he has been paid as a consultant or speaker by the following companies: Cleveland Heart Lab, Inc., Esperion, Liposciences Inc., Merck & Co., Inc., and Pfizer Inc. Dr. Hazen reports he has received research funds from Abbott, Cleveland Heart Lab, Esperion and Liposciences, Inc. Dr. Hazen has the right to receive royalty payments for inventions or discoveries related to cardiovascular diagnostics from Abbott Laboratories, Cleveland Heart Lab, Inc., Frantz Biomarkers, Liposciences, Inc., and Siemens. secondary analysis of Operations and Pelvic Muscle Training in the Management of Apical Support Loss trial. L-Carnitine dissimilation in the gastrointestinal tract of the rat. Aortic root slides were stained with Oil-red-O and counterstained with Haematoxylin. Commodity chemicals, such as acetic acid, citric acid, and ethanol are made by fermentation. Vegetarian diets: what do we know of their effects on common chronic diseases? The IP receptor is also expressed in the spinal cord and has been implicated in spinal pain transmission in response to peripheral inflammation (96). Opposing action of estrogen receptors alpha and beta on cyclin D1 gene expression. iPEEP has been measured in very few formal studies on ventilation in ARDS, and its contribution is largely unknown. An obesity-associated gut microbiome with increased capacity for energy harvest. Acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by rapid onset of widespread inflammation in the lungs. Estrogens and age-related memory decline in rodents: what have we learned and where do we go from here? For example, mast cells predominantly generate PGD2 while macrophages produce PGE2 and TXA2 (5). When ventilating at high frequencies, its contribution can be substantial, particularly in people with obstructive lung disease such as asthma or chronic obstructive pulmonary disease (COPD). However, it is unclear whether these changes contribute to the reductions in RCT. The utilization of recombinant prostanoid receptors to determine the affinities and selectivities of prostaglandins and related analogs. Analytick soubory cookie se pouvaj k pochopen toho, jak nvtvnci interaguj s webem. Springer, Cham. Federal government websites often end in .gov or .mil. To test this we initially examined data from our recently published unbiased small molecule metabolomics analyses of plasma analytes and CVD risks9. provided samples, performed human microbiota analyses, and helped interpret human microbiota data. [4], Causes may include sepsis, pancreatitis, trauma, pneumonia, and aspiration. However, controlled clinical trials to test the comparative efficacy of NSAIDs that inhibited both COXs versus COX-2 alone were never performed at scale. The effect of ERs on the cardiovascular function might be a tissue-specific since studies have found that a down-regulation of ER expression in aged human brain while both ER and ER plays neuroprotective roles in against age-related cognitive decline [114, 115]. Acute respiratory distress syndrome (ARDS) is a type of respiratory failure characterized by rapid onset of widespread inflammation in the lungs. cPGES is constitutively and abundantly expressed in the cytosol of various tissues and cells and it requires glutathione (GSH) as a cofactor (39). Cellular and molecular biology of prostacyclin synthase. Egan KM, Lawson JA, Fries S, Koller B, Rader DJ, Smyth EM, et al. The apex of the lung extends into the root of the neck, reaching shortly above the level of the sternal end of the first rib.The lungs stretch from close to the backbone Wang Z, et al. Tapering trichomes are those ending in a sharp apex. Allergic lung responses are increased in prostaglandin H synthase-deficient mice. Hematopoietic prostaglandin D2 synthase controls the onset and resolution of acute inflammation through PGD2 and 15-deoxyDelta12 14 PGJ2. Collectively, these data show that TMAO production from dietary L-carnitine in humans is dependent on intestinal microbiota. (d) Microglial cells and oligodendrocytes are not able to produce estrogen. Prostaglandins in fertility control. Activation of each promoter gives rise to alternatively spliced forms of mature mRNA with the first exon a tissue-specific, untranslated region (5'-UTR) upstream of the coding region. Mammalian class Sigma glutathione. Complications that arise from treatment in a hospital: blood clots formed by lying down for long periods of time, weakness in muscles that are used for breathing, stress ulcers, and issues with mental health and depression. Alternatively, the antagonist, unlike aspirin, might block TP activation by unconventional ligands, such as isoprostanes and HETEs. PGF2 is the most abundant prostanoid formed by human umbilical cord endothelial cells in response to laminar shear stress that upregulates expression of COX-2 (163). J.D.S. (b) Scheme of human carnitine challenge test. ER is primarily expressed in the gonadal organs (uterus, ovary, prostate, testes, and breast), but is also present at lower levels in other tissues such as bone, liver, kidney, adipose tissue, and brain. Progesterone is converted to androgens via cytochrome P450 17-hydroxylase ({"type":"entrez-protein","attrs":{"text":"P45017","term_id":"1171764","term_text":"P45017"}}P45017) and 17-beta-hydroxysteroid dehydrogenase (17-HSD) in thecal cells during the follicular phase. Hippocampal synthesis of sex steroids and corticosteroids: essential for modulation of synaptic plasticity. Jackson SP. For example, E2 activates membrane associated ER and ER to interact with metabotropic glutamate receptors (mGluRs), leading to the activation of mGluR signaling without glutamate [82]. 2007a). was supported by MOBILITAS Postdoctoral Research Grant (MJD252). Behm DJ, Ogbonna A, Wu C, Burns-Kurtis CL, Douglas SA. To better understand potential molecular mechanism(s) through which TMAO reduces RCT, we examined candidate genes and biological processes in multiple compartments (i.e. Dopamine constitutes about 80% of the catecholamine content in the brain. EP3 isoforms can couple via Gi or G12 to elevation of intracellular Ca2+, inhibition of cAMP generation, and activation of the small G protein Rho (10). Therefore, in growing follicles androgen is released from thecal cells and transported into granulose cells where it is metabolized into estrogen by aromatase [19]. Under physiological conditions, trivial amounts of these compounds are formed and their biological importance is, in many cases marginal. Allocortex; Anterior tegmental nucleus; Cerebellum; Hippocampus; ypothalamus; Isocortex; Locus coeruleus; Pontine nuclei; Preoptic area; Spinal trigeminal nucleus; Superior olive nucleus. However, there is conflicting evidence concerning the effects of estrogen treatment on CVD. Kleber HP. Questions remain regarding the effectiveness of the estrogen formulations used, dosing regimens, and routes of administration in those clinical trials, making it important to resolve the differences between the beneficial effects observed in the laboratory and the absence of such effects in clinical settings, at least as they pertain to estrogen-based therapeutic strategies for treating menopause-related cardiovascular risk factors. Parcellier A, et al. The complications associated with ERT may include hormone responsiveness with age, that is, during the menopause transition, neural sensitivity to sex steroid hormones may weaken, indicating a critical period around the time of menopause in which ERT needs to be prescribed to protect cognitive function [130, 131]. We previously reported results from a metabolomics study where small molecule analytes were sought that associated with cardiovascular risks9. Kotov A, et al. International Commission for Protection Against Environmental Mutagens and Carcinogens. 1e), post-prandial changes in endogenous (non-labeled) carnitine and TMAO were modest (Supplementary Fig. J.A.B. Recent animal studies further demonstrated that ER plays neuroprotection in PD via estrogen-dependent and --independent signaling pathways. assisted in experimental design. Thioglycollate elicited mouse peritoneal macrophages (MPMs) were harvested and cultured in RPMI 1640 supplemented with 10% FCS and penicillin/streptomycin. (2014) Novel Pharmacologic Approaches for the Treatment of ARDS. Additionally, PGE2 is fundamental to induction of a migratory DC phenotype permitting their homing to draining lymph nodes (65, 66). Students t-test or a Wilcoxon non parametric test were used to compare group means as deemed appropriate. Nagata K, Hirai H, Tanaka K, Ogawa K, Aso T, Sugamura K, Nakamura M, Takano S. CRTH2, an orphan receptor of T-helper-2-cells, is expressed on basophils and eosinophils and responds to mast cell-derived factor(s). Hirawa N, Uehara Y, Yamakado M, Toya Y, Gomi T, Ikeda T, Eguchi Y, Takagi M, Oda H, Seiki K, Urade Y, Umemura S. Lipocalin-type prostaglandin dsynthase in essential hypertension. Prostacyclin receptor signaling and early embryo development in the mouse. Cyclooxygenase in biology and disease. Resnick SM, Henderson VW. After discontinuation of antibiotics, subjects were re-challenged several weeks later. (eds) Annual Update in Intensive Care and Emergency Medicine 2014. 2b). Bethesda, MD 20894, Web Policies Neizen. People with ARDS who do not require cardiac support typically undergo venovenous ECMO. Eguchi Y, Eguchi N, Oda H, Seiki K, Kijima Y, Matsu-ura Y, Urade Y, Hayaishi O. 2a), and in a 24 hour urine collection sample (Fig. Many of these small molecules can signal the platelet through surface receptors. (2003) investigated the function of CDK inhibitor proteins (ICK/KRPs) on cell growth and differentiation by expressing ICK/KRP under a trichome-specific promoter in Arabidopsis. Yu Y, Lucitt MB, Stubbe J, Cheng Y, Friis UG, Hansen PB, Jensen BL, Smyth EM, FitzGerald GA. Prostaglandin F2alpha elevates blood pressure and promotes atherosclerosis. Haas MJ, et al. Enmark E, et al. [53] The drug is known to function by enhancing lung CD73 expression and increasing production of anti-inflammatory adenosine, such that vascular leaking and escalation of inflammation are reduced. Eguchi N, Minami T, Shirafuji N, Kanaoka Y, Tanaka T, Nagata A, Yoshida N, Urade Y, Ito S, Hayaishi O. Matsuda K, et al. Narumiya S, FitzGerald GA. Genetic and pharmacological analysis of prostanoid receptor function. Trichome patterning genes function downstream of the organ and tissue layer-specific signals. Estrogen modulates neuronal Bcl-xL expression and beta-amyloid-induced apoptosis: relevance to Alzheimer's disease. Examination of the proportion of specific bacterial genera and subject TMAO levels revealed several taxa (genus level) that simultaneously were significantly associated with both vegan/vegetarian versus omnivore status, and plasma TMAO levels (Fig. Whether there is a potential health risk for recent pervasive and rapidly growing carnitine supplement practices has not been evaluated. 1Department of Pharmacology, University of Michigan, 1150 West Medical Center Drive, 2220D MSRB III, Ann Arbor, MI 48109-5632, USA, 2Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, USA. Microorganism- and plant-produced secondary metabolites can influence disease development and suppression, as has been discussed in other parts of this chapter. Two differentially spliced variants of the sheep FP receptor ortholog have been reported: FPA and FPB, which differ from each other in the length of their C-terminal tails (139). The 1 Platelet formation in the blood. Some of the organic compounds like carbohydrates, fats, proteins, nucleic acids, chlorophylls, hemes are required for their basic metabolic processes and found C57BL/6J, Apoe/ female mice were used in the study examining the inducibility of microbiota to generate TMA and TMAO following carnitine feeding. The marked effect of dietary carnitine on enhanced TMA and TMAO production from a carnitine challenge (d3-(methyl)carnitine by gavage) suggested that chronic carnitine supplementation may significantly alter intestinal microbial composition with enrichment of taxa better suited for TMA production from carnitine. Boxes represent the 25th, 50th, and 75th percentile of plasma carnitine and the whiskers represent the 10th and 90th percentile. Inflammation is the immune systems response to infection and injury and has been implicated in the pathogeneses of arthritis, cancer and stroke, as well as in neurodegenerative and cardiovascular disease. A systems approach to hemostasis: 4. Essential oils and their components have activity against a variety of targets, particularly the membrane and cytoplasm, and in some cases, they completely change the morphology of the cells. A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Given the contrasting effects of prostanoids, should we move down the pathway to get a more targeted and safer response? While the primary function of the platelet is thought to be hemostasis, thrombosis, and wound healing through a complex activation process leading to integrin activation and formation of a core and shell at the site of injury, other physiological roles for the platelet exist including immunity and communication with other cells and tissue in the vessel. mPGES-1 is a member of the MAPEG (membrane-associated proteins involved in eicosanoid and glutathione metabolism) superfamily and like cPGES, it requires GSH as cofactor (41). This sampling of the environment may serve the purpose of presenting the foreign virus or bacteria to other immune cells. As with cyclopentanone prostanoids, many arachidonate derivatives, including transcellular products, when synthesized and administered as exogenous compounds, can promote resolution in models of inflammation. Studies found that ER is the dominant receptor involved in neuroprotection in PD, while ER plays little role in neuroprotection [155, 156]. Furthermore, our recent studies not only confirmed with the benefit effect of early ERT, but also showed that the level of brain estrogen level determines the effect of estrogen therapy in protect against AD pathology in animal model [107]. Altmann SW, et al. As shown in figure 2, the human aromatase gene CYP19 comprises a 93 kb 5'-regulatory region and a 30 kb 3'-coding region. Interplay between AP-1 and estrogen receptor alpha in regulating gene expression and proliferation networks in breast cancer cells. gall bladder removal, bowel resection) surgery. Similarly, arthritis models exhibit a significant reliance on either the COX-1 or COX-2 isoforms for the development of clinical synovitis. [42] Other triggers include mechanical ventilation, sepsis, pneumonia, Gilchrist's disease, drowning, circulatory shock, aspiration, traumaespecially pulmonary contusionmajor surgery, massive blood transfusions,[43] smoke inhalation, drug reaction or overdose, fat emboli and reperfusion pulmonary edema after lung transplantation or pulmonary embolectomy. Doses less than 100 mg per day have equivalent effects on platelet biology phenylbenzoquinone zymosan. 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