This mouse study investigated the effects of the highly selective 5-HT₂ receptor agonist (R)-DOI (0.01-1mg/kg) in a mouse model of allergic asthma. They demonstrate that inhaled (R)-DOI has potent anti-inflammatory effects and blocks the development of allergic asthma through the activation of the serotonin 5-HT2A receptor subtype.
Asthma is an inflammatory disease of the lung characterized by airways hyper-responsiveness (AHR), inflammation, and mucus hyperproduction. Current mainstream therapies include bronchodilators that relieve bronchoconstriction and inhaled glucocorticoids to reduce inflammation. The small molecule hormone and neurotransmitter serotonin has long been known to be involved in inflammatory processes; however, its precise role in asthma is unknown. We have previously established that activation of serotonin 5-hydroxytryptamine (5-HT)2A receptors has potent anti-inflammatory activity in primary cultures of vascular tissues and in the whole animal in vasculature and gut tissues. The 5-HT2A receptor agonist, (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI] is especially potent. In this work, we have examined the effect of (R)-DOI in an established mouse model of allergic asthma. In the ovalbumin mouse model of allergic inflammation, we demonstrate that inhalation of (R)-DOI prevents the development of many key features of allergic asthma, including AHR, mucus hyperproduction, airways inflammation, and pulmonary eosinophil recruitment. Our results highlight a likely role of the 5-HT2 receptors in allergic airways disease and suggest that 5-HT2 receptor agonists may represent an effective and novel small molecule-based therapy for asthma.
Serotonin (5-HT) acts through multiple receptor subtypes and is implicated in various physiological and immune processes. Prior work has shown that the 5-HT2A receptor, best known for roles in the central nervous system and as the target of classic hallucinogens, is also expressed in immune-related tissues and certain pulmonary cell types. Nau and colleagues previously reported potent anti-inflammatory effects of 5-HT2A receptor agonists in vitro and in vivo, particularly with the high-affinity agonist (R)-DOI, which blocks expression of multiple proinflammatory markers and pathways. This study set out to test whether activation of 5-HT2 receptors by inhaled (R)-DOI can prevent key features of allergic airways disease. Using the well-established ovalbumin (OVA) mouse model of allergic asthma, the investigators examined whether pulmonary delivery of (R)-DOI blocks airways hyperresponsiveness (AHR), mucus hyperproduction, pulmonary inflammation and eosinophil recruitment, and they profiled relevant cytokine and chemokine gene expression in the lung.
Papers cited by this study that are also in Blossom
Moya, P. R., Berg, K. A., Gutiérrez-Hernandez, M. A. et al. · Journal of Pharmacology and Experimental Therapeutics (2007)
Papers in Blossom that reference this study
Flanagan, T. W., Foster, T. P., Galbato, T. E. et al. · ACS Pharmacology and Translational Science (2024)
Mason, N. L., Szabo, A., Kuypers, K. P. C. et al. · Brain Behavior and Immunity - Health (2023)
The study used the OVA-induced allergic asthma model in male mice aged 6–8 weeks. Mice were sensitised by intraperitoneal injection of 20 μg OVA emulsified in alum on days 0 and 14, then challenged with a 1% (wt/vol) OVA aerosol for 20 minutes on days 24–26. Thirty minutes before each aerosol challenge mice received nose-only inhalation of (R)-DOI at either 0.01 mg/kg or 1.0 mg/kg, or vehicle control, delivered with an ultrasonic nebuliser. Pulmonary physiology was assessed on day 28. Two complementary methods were used: the forced oscillation technique in anaesthetised, mechanically ventilated animals (FlexiVent) with tidal volume 10 ml/kg and frequency 2.5 Hz, and whole-body plethysmography in awake mice recording peak enhanced pause (PenH). Bronchoconstrictor responses were evoked by serial aerosolised methacholine (MeCh) challenges; MeCh concentrations differed slightly between methods (forced oscillation up to 50 mg/ml, whole-body plethysmography up to 100 mg/ml). Bronchoalveolar lavage fluid (BALF) was collected after pulmonary testing on day 28 for total and differential cell counts; two blinded observers classified cells and at least 200 cells were counted per animal. Lung histopathology was performed on paraffin sections stained with Periodic acid–Schiff (PAS) for mucus and haematoxylin and eosin for morphology and inflammation. BALF total protein was measured by BCA assay. Pulmonary gene expression of a panel of cytokines and chemokines (Il-4, Il-5, Il-6, Il-10, Il-13, Tnfα, Mcp-1, and Gm-csf) was quantified by quantitative PCR using Roche LightCycler instrumentation and analysed by the ΔΔCT method normalised to Gapdh. Total and OVA-specific serum IgE were measured, although assay details are not clearly reported in the extracted text. Statistical analyses were performed using GraphPad Prism. The extracted text does not clearly report group sizes or specific statistical tests used for individual comparisons.
In both measures of airway function, OVA-sensitised and challenged mice developed significant AHR as expected. Pulmonary administration of (R)-DOI prior to each OVA challenge effectively prevented this increase in airway responsiveness. Mice treated with either 0.01 mg/kg or 1.0 mg/kg (R)-DOI showed airway responses that were not significantly different from naïve controls by both forced oscillation and whole-body plethysmography. Histological examination revealed pronounced peribronchial inflammation and mucus hyperproduction in OVA-only mice. Pretreatment with 1.0 mg/kg (R)-DOI produced very little peribronchial inflammation or mucus, whereas the low dose of 0.01 mg/kg led to a significant reduction in inflammation and mucus compared to OVA alone but did not fully normalise histology. Cellular analysis of BALF showed that OVA provoked a marked increase in total recovered cells driven largely by eosinophils. Both (R)-DOI doses significantly reduced total BALF cell numbers and eosinophil counts relative to OVA-only mice. Eosinophil counts in the (R)-DOI groups were higher than in naïve mice but not significantly different from naïve. A non-significant trend toward reduced neutrophils was observed in (R)-DOI treated mice. Measures of lung vascular/epithelial leak and systemic humoral responses were not altered by (R)-DOI. BALF total protein was elevated in OVA mice versus naïve controls, and (R)-DOI did not reduce BALF protein compared with OVA-only. Similarly, OVA increased total and OVA-specific serum IgE, and these increases were not affected by (R)-DOI treatment. At the transcriptional level, OVA increased lung mRNA for several Th2 and innate cytokines and chemokines (Il-4, Il-5, Il-10, Il-13, Mcp-1, and Gm-csf), with Il-6 and Tnfα showing non-significant trends. (R)-DOI did not alter the OVA-induced increases in Il-4 or Il-10. In contrast, (R)-DOI significantly repressed OVA-induced Mcp-1, Il-13 and Il-5 expression and completely blocked the increase in Gm-csf. Although Il-6 was not significantly upregulated by OVA in this dataset, (R)-DOI significantly reduced Il-6 expression in OVA-treated mice.
Nau and colleagues interpret their findings as evidence that selective activation of serotonin 5-HT2 receptors with inhaled (R)-DOI has potent anti-inflammatory effects in the lung and prevents the development of allergic airways disease in the OVA mouse model. They emphasise that previous work indicates the anti-inflammatory actions of (R)-DOI are mediated via the 5-HT2A receptor subtype, and the authors detected 5-HT2A receptor mRNA in whole lung tissue. Two doses were examined: 1.0 mg/kg, comparable to doses used in behavioural studies, and a much lower 0.01 mg/kg dose chosen to test the compound's predicted super-potency; both doses produced anti-inflammatory effects. The investigators propose that the therapeutic site of action is pulmonary tissue, acting on resident activated T cells and/or innate immune cells. Support for this mechanism includes repression by (R)-DOI of key mediators of eosinophil recruitment and Th2 responses, including Il-5, Gm-csf and Mcp-1, and the observed blockade of eosinophil recruitment, mucus hyperproduction and AHR. Because (R)-DOI did not reduce BALF protein or modulate total or OVA-specific IgE, the authors suggest the drug acts on activated rather than naïve immune populations and that its protective effects are likely non-mast-cell dependent. The discussion contrasts these results with earlier reports that implicated 5-HT2A receptors in promoting AHR; the authors note those studies used the relatively non-selective antagonist ketanserin, which complicates interpretation. Two explanations are offered for the apparent discrepancy: selective activation of 5-HT2 receptors may avoid engagement of other serotonin receptor subtypes that drive inflammation, and (R)-DOI may act as a functionally selective ligand at 5-HT2A receptors, recruiting anti-inflammatory signalling pathways that endogenous serotonin does not. The authors acknowledge several uncertainties: they were unable in this study to directly validate the receptor subtype mediating the effect, systemic administration of (R)-DOI was not tested, and the precise downstream signalling pathways remain to be elucidated. Concluding, the study identifies a previously unrecognised functional role for 5-HT2 receptor activation in the lung and proposes that selective 5-HT2A agonists such as (R)-DOI might represent a novel small-molecule therapeutic approach for asthma, effective at doses well below those required to cause behavioural or cardiovascular adverse effects.
Serotonin (5-hydroxytryptophan, 5-HT) is a ubiquitous small hormone molecule present in nearly all eukaryotes that mediates a wide spectrum of physiological processes. In mammals it exerts its action through 14 different receptor subtypes that comprise seven distinct families (5-HT 1-7 ). All but one family, the ligand-gated 5-HT 3 receptor ion channel, are G-protein coupled receptors. The 5-HT 2A receptor is primarily known for its role in mediating complex cognitive behaviors within the central nervous system, and for mediating physiological processes such as vasoconstriction in the periphery. Interestingly, the 5-HT 2A receptor is the primary target of classic hallucinogenic drugs like lysergic acid diethylamide (LSD), which produces intoxicating effects. Although 5-HT 2A receptor mRNA is expressed at higher levels in immune related tissues such as spleen, thymus, and peripheral circulating lymphocytes compared to other serotonin receptor subtypes (i.e. 5-HT 1A , 5-HT 1D , 5-HT 2C , 5-HT 4 , 5-HT 5A , and 5-HT 5B ), its precise role in inflammatory processes is not well defined. With regard to of the potential role of serotonin in asthma, 5-HT 2A receptors are functionally expressed in activated CD4 + T cells, alveolar macrophages, eosinophils, and lung epithelial and smooth muscle cells,. In fact, migration of eosinophils in allergic asthma has been recently shown to be dependent on 5-HT 2A receptor activation, and 5-HT 2 receptors have been implicated in platelet function relevant to allergic asthma. We recently reported that 5-HT 2A receptor agonists potently inhibit inflammation in vitro. The anti-inflammatory effects of one particular 5-HT 2A receptor agonist, (R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(R)-DOI], is extremely potent, with an EC 50 of ~15 picomolar. Through activation of the 5-HT 2A receptor, (R)-DOI blocks the expression and activation of proinflammatory markers including expression of chemokines (e.g. MCP-1), cellular adhesion molecules (ICAM1 and VCAM1), cytokines (e.g. IL-6), nitric oxide synthase, and activation/nuclear translocation of NF-kB in a variety of cell types, including primary aortic smooth muscle cells. We have translated these in vitro findings to a whole animal mouse model of inflammation by demonstrating that (R)-DOI, also through 5-HT 2A receptor activation, has potent antiinflammatory effects when administered systemically prior to systemically administered TNF-α. These effects are most pronounced in the vasculature and the gut, where preadministration of (R)-DOI blocks TNF-α induced increases in proinflammatory gene and protein expression, including circulating IL-6. In an effort to extend our findings to the potential use of (R)-DOI as a therapeutic in inflammatory airways disease, herein we examine the ability of (R)-DOI to block the key features of allergic asthma in the well-established mouse model of ovalbumin (OVA) induced allergic asthma. In this model, mice are sensitized and challenged with inhaled chicken OVA peptide to induce a phenotype resembling human asthma, including airways hyperresponsiveness in response to methacholine (MeCh), mucus hyperproduction, and pulmonary inflammation characterized by eosinophilia. We show here that inhaled (R)-DOI blocks airways hyper-responsiveness, recruitment of eosinophils to the lung, mucus hyperproduction, and inflammatory airway remodeling. We speculate that, 5-HT 2 receptor agonism may represent a novel therapeutic strategy for asthma. Induction of allergic inflammatory airways disease (i.e. the OVA mouse model of asthma). Mice (male; 6-8 weeks old) were sensitized and challenged with chicken ovalbumin grade V (OVA; Sigma, St. Louis, MO) as previously described (4). Briefly, mice were sensitized by an intraperitoneal injection (100 ul) of 20 μg OVA emulsified in 2 ml Imject Alum (Al [OH]3/Mg [OH]2; Pierce Rockford, IL) on days 0 and 14. Mice were subsequently challenged with an OVA aerosol generated using an ultrasonic nebulizer (PariNeb Pro Nebulizer) using a 1% (wt/vol) OVA solution in saline for 20 min on days 24, 25 and 26. Thirty minutes prior to each OVA challenge each mouse was treated with one of two different concentrations of (R)-DOI (nose-only inhalation of 0.01 mg/kg or 1.0 mg/kg) or vehicle control using an ultrasonic nebulizer (Aerogen, Galway, Ireland).
Measurement of airway inflammation, pulmonary mechanics, and BALF cellularity. Pulmonary function testing, BAL and tissue harvests were performed on day 28 (when mice were 10 to 12 weeks of age). For the forced oscillation method, pulmonary resistance was measured as previously described. In brief, anesthetized animals were mechanically ventilated with a tidal volume of 10 ml/kg and a frequency of 2.5 Hz using a computer-controlled piston ventilator (Flexivent, SCIREQ; Montreal, Canada). Bronchial tone was determined in response to increasing concentrations of the aerosolized bronchoconstrictor methacholine (MeCh, at 0, 6.25, 12.5, 25 and 50 mg/ml in isotonic saline). The single compartment model was used to calculate airway resistance values, and peak values obtained after each MeCh challenge were plotted. On protocol day 28, bronchoalveolar lavage fluid (BALF) was harvested after pulmonary function testing and analyzed for cellularity as previously described (3). Differential cell counts were performed by two blinded observers using standard morphological criteria to classify individual leukocyte populations. All mice from each group were used for these analyses, and over 200 cells were counted per animal. For the whole body method, airway hyperresponsiveness to MeCh (0, 6.25, 12.5, 25, 50, and 100 mg/ml in isotonic saline) was measured using whole body plethysmography (Buxco Electronics, Troy, NY and EMKA Technologies, Falls Church, VA) and performed as described previously. Mice were exposed to aerosolized MeCh for 1 minute at each dose and peak enhanced pause (PenH) response was recorded for 3 minutes. The max PenH was averaged for each dose and data were plotted as percent change from vehicle controls. Lung histopathology. Lungs were isolated and prepared as previously described. Sections (4 μm) were cut from paraffin embedded lungs and stained with Periodic acid-Schiff (PAS) staining to visualize mucus and imaged as previously described. Adjacent sections were stained with hematoxylin and eosin to visualize airway morphology and cellular inflammation.
Total protein was measured from BALF isolated on Day 28 using the Pierce BCA Protein Assay kit following manufacturer's directions (Thermo Scientific # 23228, Rockford, IL). Roche LightCycler 480II LC (Roche, Indianapolis, IN). Gene expression levels were calculated using the ΔΔC T method and normalized to internal Gapdh expression as determined using the Mouse Gapdh Gene Assay (Roche Diagnostics, Cat. no. 05046211001) in multiplex format.
Statistics. All statistical analysis was performed using GraphPad Prism (La Jolla, CA). In Figure
Pulmonary administration of (R)-DOI is effective in preventing airways hyperresponsiveness (AHR) in a mouse model of allergic asthma. Following OVA sensitization and challenge, we measured airways resistance by two different methods in separate groups of mice. For the first method we used the forced oscillation technique, and in the second method whole body plethysmography in awake freely moving mice. As expected, mice receiving only OVA develop significant AHR in both methods (Figure). Mice pretreated with inhaled (R)-DOI at either 0.01 (Figureand 1B) or 1.0 mg/kg (Figureand) prior to OVA challenge display airways responsiveness not significantly different from naïve as measured by either method. (R)-DOI prevents pulmonary inflammation and mucus hyperproduction. Histopathological analysis of lung sections from the different treatment groups demonstrated that, as expected, OVA mice develop significant pulmonary inflammation and mucus. Animals treated with (R)-DOI (1.0 mg/kg) prior to OVA exposure exhibit very little peribronchial inflammation or mucus. Mice treated with two orders of magnitude less (R)-DOI (0.01 mg/kg) demonstrate significantly reduced inflammation and mucus production compared to the OVA only exposed lungs (Figuresand). (R)-DOI reduces pulmonary inflammation and BALF eosinophilia. Pulmonary inflammation is a common feature of asthma and is partly responsible for increased AHR. To associate (R)-DOI treatment and decreased AHR as well as normal appearing histological results with lack of inflammation, we performed cell differential counts on BALF cell populations for each mouse in each group. As expected, OVA induced a significant increase in the total number of cells recovered in the BALF when compared to naïve and (R)-DOI treated animals. A large fraction of the BALF cellularity was due to elevated numbers of eosinophils (Figure). Total BALF cell numbers and eosinophil numbers for naïve, 0.01 mg/kg DOI + OVA and 1.0 mg/kg DOI + OVA were significantly lower than the OVA-only mice (Figure). Although the eosinophil numbers for the (R)-DOI treated mice were greater than those of naïve mice they were not significantly different. There is a trend for a decrease in the neutrophil numbers in (R)-DOI treated mice compared to AVA treated mice, however the difference was not significant. (R)-DOI does not alter lung leak or plasma IgE levels. Increased protein content of the BALF is a hallmark of asthma and the OVA model. Analysis of BALF total protein by BCA assay from different treatment groups revealed a significant increase between naïve and OVA groups but showed no difference between mice treated with (R)-DOI + OVA and those animals that were treated with OVA only (Figure). The OVA model characteristically produces increased serum levels of IgE and OVA-specific IgE, therefore we tested the effects of (R)-DOI on total IgE and OVA specific IgE. In both cases, we measured a significant increase between naïve and OVA treated groups. (R)-DOI treatment, however, had no effect on either total IgE or OVA-specific IgE as induced by OVA (Figure). (R)-DOI suppresses expression of genes involved in the T-cell and innate immune cell response. A panel of cytokines and chemokines typically involved in asthma and the OVA model (Il-4, Il-5, Il-6, Il-10, Il-13, Tnfα, Mcp-1, and Gm-csf) was examined in the lungs by QPCR. There were, as anticipated, significant increases in mRNA for Il-4, Il-5, Il-10, Il-13, Mcp-1 and Gm-csf with OVA treatment compared to naïve mice. There was a trend that did not reach significance for Il-6 and Tnfα expression. (R)-DOI had no effect on the increased expression levels of OVA induced Il-4, or Il-10. Interestingly, (R)-DOI treatment significantly repressed the OVA-induced increases in mRNA expression for Mcp-1, Il-13, Il-5, and completely blocked the increase in Gm-csf (Figure). Although Il-6 expression was not significantly upregulated in the OVA group compared to vehicle control, (R)-DOI did significantly reduce Il-6 expression levels in OVA treated mice, as expected from our previous studies in different inflammatory models (Figure).
To determine if serotonin 5HT 2 receptor activation with (R)-DOI is an effective mechanism to treat a pathological inflammatory disease, we investigated the effects of the highly selective 5-HT 2 receptor agonist (R)-DOI in a mouse model of allergic asthma. Building upon our earlier in vitro and in vivo studies, we demonstrate here that inhaled (R)-DOI has potent anti-inflammatory effects and blocks the development of allergic asthma in the OVA mouse model. Importantly, we have already established that the anti-inflammatory effects of (R)-DOI in vitro and in vivo are mediated through activation of the serotonin 5-HT 2A receptor subtype. Here, we tested two different doses of (R)-DOI. The 1.0 mg/kg dose is in the range of that used in typical behavioral experiments. The very low dose of 0.01 mg/kg was chosen to test the super potency of (R)-DOI predicted by our previous cellular studies. Antiinflammatory effects of this very low dose were also observed in our recent in vivo study examining the ability of (R)-DOI to block the effects of systemic administration of TNF-α. Because activation of the 5-HT 2A receptor subtype, and not the 5-HT 2C receptor subtype, was found to be necessary for the anti-inflammatory effects of (R)-DOI in our previous studies, we hypothesized that the effects of (R)-DOI against allergic asthma were also mediated through 5-HT 2A receptor activation. Although we were not able to validate this here, we have confirmed the presence of 5-HT 2A receptor mRNA on whole lung tissue. Furthermore, the expression of 5-HT 2A receptors has been reported in airway smooth muscle cells (2) and alveolar macrophages, and although naïve T cells do not express high levels of the 5-HT 2A receptor, activated T cells do express high levels of 5-HT 2A receptor mRNA. We suggest that (R)-DOI's site of therapeutic action in this model is the pulmonary tissues, including resident activated T-cell populations and/or innate immune cells. The major components of allergic asthma in humans include AHR, pulmonary inflammation, and mucus hyperproduction. In addition, eosinophils, which release cytotoxic mediators and leukotrienes are recruited in large numbers to the lungs of asthmatic individuals (37). Eosinophil production, chemotaxis, and survival are controlled by RANTES (CCL5), macrophage inflammatory protein 1α, eotaxins, IL-5, and GM-CSF. IL-5 and GM-CSF are derived from activated pulmonary epithelial cells, eosinophils themselves, and activated T-lymphocytes. IL-5 and GM-CSF are molecules important in the development of asthma, and are increased in serum and BALF of asthmatics in the clinic. Significantly, our data show that both genes are suppressed by administration of (R)-DOI in the OVA mouse model. The role of eosinophils in asthma is both direct, causing bronchoconstriction and destruction to airways, and indirect by provoking degranulation of mast cells and basophils. We demonstrate here that (R)-DOI blocks recruitment of eosinophils to the lung, prevents mucus cell mucus hyperproduction, blocks AHR, and represses Th 2 and innate immune cell gene expression (e.g. Il-5, and Mcp-1). We directly delivered (R)-DOI to the lung using inhalation techniques in these experiments, and it remains to be determined if systemically injected (R)-DOI has the same or similar effects on the development of asthma. Importantly, effective levels of (R)-DOI administered by this route (inhalation) are orders of magnitude less than those necessary to produce either behavioral intoxication, as indicated by the classical head twitch response, or airways constriction in mice (>10 mg/kg inhaled; data not shown). Although the presence of 5-HT 2A receptor mRNA has been demonstrated in pulmonary tissues by our lab and others, the role of this receptor in the lung has remained largely undefined. A few reports have suggested that the 5-HT 2A receptor mediates AHR in allergic asthma. However, these studies used the antagonist ketanserin, which is non-selective in rodents for 5-HT 2 receptors and also has high affinity for histamine H1 and α-adrenergic receptors, to block the effects of serotonin. This makes it difficult to interpret results using ketanserin. In any case, these reports indicated that serotonin activation of 5-HT 2A receptors contribute to AHR, not prevent it. Serotonin itself has been implicated in airways inflammation in allergic asthma by acting as a critical factor to recruit inflammatory cells and prime Th 2 responses by activation of bone marrow derived dendritic cells, although the receptor(s) mediating these effects remain unknown. Conversely, blockade of serotonin receptors with a non-selective antagonist for multiple subtypes has demonstrated antiasthma effects in the OVA model. Why then, if serotonin appears to have a proinflammatory effect in the lung, does activation of 5-HT 2 receptors with (R)-DOI have an anti-inflammatory effect? One possibility is that selective activation of 5-HT 2 receptors with (R)-DOI avoids activation of other serotonin receptor types responsible for the inflammatory response. A more likely explanation is that (R)-DOI, which has a much higher affinity for the 5-HT 2 receptors than serotonin, is acting as a functionally selective ligand and recruiting anti-inflammatory effector pathways that serotonin itself does not. Significantly, DOI has already been demonstrated to activate different signaling pathways than serotonin at the 5-HT 2A receptor in vivo to modulate biological responses. It is unlikely that the therapeutic mechanistic site of action of (R)-DOI is on the Bcell or the antigen presenting cell (APC) as (R)-DOI has no effect on OVA-induced Il-4 gene expression. Recent reports indicate that IgE-dependent mast cell activation is involved in the development of AHR. That (R)-DOI has no measureable effect on humoral IgE production, yet prevents AHR, suggests that (R)-DOI is acting on activated rather than naïve T cells to block AHR through non-mast cell dependent mechanisms.
Mcp-1 and Gm-csf mRNA production, the therapeutic target may also include innate immune cells. There is also the possibility that (R)-DOI may be acting on the naïve CD4 + population, however, naïve T cells do not express high levels of 5-HT 2A receptor mRNA until activated. Our data demonstrate that (R)-DOI treatment significantly inhibits the OVA-induced expression of Th 2 related genes that include Il-13, Il-5, and Gm-csf in the lung. Interestingly, vascular (or more likely epithelial) permeability is not improved with (R)-DOI, as total protein in the BALF is not reduced compared to OVA alone. We propose a model, shown in Figure, where the pool of 5-HT 2A receptors activated by (R)-DOI that responds with anti-inflammatory properties could reside on activated Th 2 cells and/or innate immune cells. In this proposed model, 5-HT 2A receptor activation would lead to reduced IL-5, GM-CSF, and MCP-1 secretion, in turn decreasing eosinophil recruitment, Th 2 polarization, and Il-13 production. Overall, these effects would combine to reduce inflammation and AHR. The precise cellular signaling pathways, however, remain to be elucidated. In conclusion, we have identified an important and new functional role of 5-HT 2 receptors in the lung. (R)-DOI activation of serotonin 5-HT 2 receptors potently prevents the development of a clinically relevant mouse model of allergic asthma at drug levels far below those necessary to invoke adverse cardiovascular or behavioral effects. Based on our previous in vitro and in vivo studies, we predict that it is the 5-HT 2A receptor that is the therapeutic target of (R)-DOI in our model. Our results demonstrate that activation of 5-HT 2 receptors differentially regulates Th 2 signaling, innate cytokine responses, and other relevant inflammatory effector pathways, and that selective activation with (R)-DOI, or perhaps other 5-HT 2A agonists in its class, represent a novel small molecule based therapeutic strategy for the treatment of asthma.
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