Indoor exposure to phthalates and polycyclic aromatic hydrocarbons (PAHs) to Canadian children: the Kingston allergy birth cohort.

BACKGROUND: Canadian children are widely exposed to phthalates and polycyclic aromatic hydrocarbons (PAHs) from indoor sources. Both sets of compounds have been implicated in allergic symptoms in children. OBJECTIVE: We characterize concentrations of eight phthalates and 12 PAHs in floor dust from the bedrooms of 79 children enrolled in the Kingston Allergy Birth Cohort (KABC). METHOD: Floor dust was collected from the bedrooms of 79 children who underwent skin prick testing for common allergens after their first birthday. Data were collected on activities, household, and building characteristics via questionnaire. RESULTS: Diisononyl phthalate (DiNP) and phenanthrene were the dominant phthalate and PAH with median concentrations of 561 µg/g and 341 ng/g, respectively. Benzyl butyl phthalate (BzBP) and chrysene had the highest variations among all tested homes, ranging from 1-95% to 1-99%, respectively. SIGNIFICANCE: Some phthalates were significantly associated with product and material use such as diethyl phthalate (DEP) with fragranced products and DiNP and DiDP with vinyl materials. Some PAHs were significantly associated with household characteristics, such as benzo[a]pyrene with smoking, and phenanthrene and fluoranthene with the presence of an attached garage. Socioeconomic status (SES) had positive and negative relationships with some concentrations and some explanatory factors. No significant increases in risk of atopy (positive skin prick test) was found as a function of phthalate or PAH dust concentrations.

Indoor measurements of air pollutants in residential houses in urban and suburban areas: Indoor versus ambient concentrations.

Indoor exposure to air pollutants was assessed through 99 visits to 51 homes located in downtown high-rise buildings and detached houses in suburban and rural areas. The ambient concentrations of ultrafine particles (UFP), black carbon (BC), particulate matter smaller than 2.5 µm in diameter (PM2.5), and trace elements were concurrently measured at a central monitoring site in downtown Toronto. Median hourly indoor concentrations for all measurements were 4700 particles/cm3 for UFP, 270 ng/m3 for BC, and 4 µg/m3 for PM2.5, which were lower than ambient outdoor levels by a factor of 2-3. Much higher variability was observed for indoor UFP and BC across the homes compared to ambient levels, mostly due to the influence of indoor cooking emissions. Traffic emissions appeared to have a strong influence on the indoor background (i.e., outdoor-originated) concentrations of BC, UFP, and some trace elements. Specifically, 85% and 34% of the indoor concentrations of BC and UFP were predominantly from outdoor sources, respectively. Moreover, a positive correlation was observed between indoor concentrations of BC and UFP and total road length within a 300 m buffer zone. There was no significant decrease in indoor air pollution with increasing floor level among high-rise residences. In addition to the influence of outdoor sources on indoor air quality, indoor sources contributed to elevated concentrations of K, Ca, Cr, and Cu. A factor analysis was performed on trace elements, UFP, and BC in homes to further resolve possible sources. Local traffic emissions, soil dust, biomass burning, and regional coal combustion were identified as outdoor-originated sources, while cooking emissions was a dominant indoor source. This study highlights how outdoor sources can contribute to chronic exposure in indoor environments and how indoor activities can be associated with acute exposure to temporally varying indoor-originated air pollutants.

The Kingston Allergy Birth Cohort: Exploring parentally reported respiratory outcomes through the lens of the exposome.

BACKGROUND: The Kingston Allergy Birth Cohort (KABC) is a prenatally recruited cohort initiated to study the developmental origins of allergic disease. Kingston General Hospital was chosen for recruitment because it serves a population with notable diversity in environmental exposures relevant to the emerging concept of the exposome. OBJECTIVE: To establish a profile of the KABC using the exposome framework and examine parentally reported respiratory symptoms to 2 years of age. METHODS: Data on phase 1 of the cohort (n = 560 deliveries) were compiled, and multivariate Cox proportional hazards regression models were used to determine associations with respiratory symptoms. RESULTS: The KABC exhibits diversity within the 3 exposome domains of general external (socioeconomic status, rural or urban residence), specific external (cigarette smoke, breastfeeding, mold or dampness), and internal (respiratory health, gestational age), as well as significant associations between exposures from different domains. Significant associations emerged between parental reports of wheeze or cough without a cold and prenatal cigarette smoke exposure, mold or dampness in the home, and the use of air fresheners in the early-life home environment. Breastfeeding, older siblings, and increased gestational age were associated with decreased respiratory symptoms. CONCLUSION: The KABC is a unique cohort with diversity that can be leveraged for exposomics-based studies. This study found that all 3 domains of the exposome had effects on the respiratory health of KABC children. Ongoing studies using phase 1 of the KABC continue to explore the internal exposome through allergy skin testing and epigenetic analyses and the specific external domain through in-home environmental analyses, air pollution modeling, and ultimately potential convergences within and among domains.

Development of a Novel Simulation Reactor for Chronic Exposure to Atmospheric Particulate Matter.

Epidemiological studies have shown that air pollution is associated with the morbidity and mortality from cardiopulmonary diseases. Currently, limited experimental models are available to evaluate the physiological and cellular pathways activated by chronic multi-pollutant exposures. This manuscript describes an atmospheric simulation reactor (ASR) that was developed to investigate the health effects of air pollutants by permitting controlled chronic in vivo exposure of mice to combined particulate and gaseous pollutants. BALB/c mice were exposed for 1 hr/day for 3 consecutive days to secondary organic aerosol (SOA, a common particulate air pollutant) at 10-150 µg/m3, SOA (30 µg/m3) + ozone (65 ppb) or SOA + ozone (65 ppb) + nitrogen dioxide (NO2; 100 ppb). Daily exposure to SOA alone led to increased airway hyperresponsiveness (AHR) to methacholine with increasing SOA concentrations. Multi-pollutant exposure with ozone and/or NO2 in conjunction with a sub-toxic concentration of SOA resulted in additive effects on AHR to methacholine. Inflammatory cell recruitment to the airways was not observed in any of the exposure conditions. The ASR developed in this study allows us to evaluate the chronic health effects of relevant multi-pollutant exposures at 'real-life' levels under controlled conditions and permits repeated-exposure studies.

Controlled Allergen Challenge Facilities and Their Unique Contributions to Allergic Rhinitis Research.

The aim of this study is to review advances in basic and clinical allergic rhinitis (AR) research over the past decade that have been conducted using controlled allergen challenge facility (CACF) models of allergen challenge. Databases, including PubMed, Medline, and Web of Science were searched for articles employing an ambient pollen exposure in a controlled facility to study AR, published between 2004 and the present date, using the terms as follows: CACF, Environmental Exposure Unit (EEU), Vienna Challenge Chamber (VCC), Fraunhofer Institute Environmental Challenge Chamber, Atlanta Allergen Exposure Unit, Biogenics Research Chamber, Allergen BioCube, Chiba and Osaka Environmental Challenge Chamber, exposure unit, challenge chamber, or environmental exposure chamber. Articles were then selected for relevance to the goals of the present review, including important contributions toward clinical and/or basic science allergy research. CACFs offer sensitive, specific, and reproducible methodology for allergen challenge. They have been employed since the 1980s and offer distinct advantages over traditional in-season multicentre trials when evaluating new treatments for AR. They have provided clinically applicable efficacy and pharmacologic information about important allergy medications, including antihistamines, decongestants, antileukotrienes, immunotherapies, and nasal steroids. CACF models have also contributed to basic science and novel/experimental therapy research. To date, no direct studies have been conducted comparing outcomes from one CACF to another. Over the past decade, CACF models have played an essential role in investigating the pathophysiology of AR and evaluating new therapies. The future opportunities for this model continue to expand.

Plasma arginine metabolites reflect airway dysfunction in a murine model of allergic airway inflammation.

L-arginine metabolism is important in the maintenance of airway tone. Shift of metabolism from the nitric oxide synthase to arginase pathways contributes to the increased airway responsiveness in asthma. We tested the hypothesis that systemic levels of L-arginine metabolites are biomarkers reflective of airway dysfunction. We used a mouse model of acute allergic airway inflammation to OVA that manifests with significant airway hyperresponsiveness to methacholine. To determine tissue arginase activity in vivo, the isotopic enrichment of an infused L-arginine stable isotope and its product amino acid L-ornithine were measured in lung and airway homogenates using liquid chromatography-tandem mass spectrometry. Tissue and plasma concentrations of other L-arginine metabolites, including L-citrulline and symmetric and asymmetric dimethylarginine, were measured and correlated with lung arginase activity and methacholine responsiveness of the airways. The effectiveness of intratracheal instillation of an arginase inhibitor (boronoethylcysteine) on pulmonary arginase activity and circulating concentrations of L-arginine metabolites was also studied. We demonstrate that 1) plasma indexes of L-arginine bioavailability and impairment of nitric oxide synthase function correlate with airway responsiveness to methacholine; 2) plasma levels of L-ornithine predict in vivo pulmonary arginase activity and airway function; and 3) acute arginase inhibition reduces in vivo pulmonary arginase activity to control levels and normalizes plasma L-ornithine, but not L-arginine, bioavailability in this model. We conclude that plasma L-ornithine may be useful as a systemic biomarker to predict responses to therapeutic interventions targeting airway arginase in asthma.

Add-on histamine receptor-3 antagonist for allergic rhinitis: a double blind randomized crossover trial using the environmental exposure unit.

BACKGROUND: Oral antihistamines that target the histamine receptor-1, such as fexofenadine, offer suboptimal relief of allergic rhinitis-associated nasal congestion. Combinations with oral sympathomimetics, such as pseudoephedrine, relieve congestion but produce side effects. Previous animal and human studies with histamine receptor-3 antagonists, such as PF-03654764, demonstrate promise. METHODS: Herein we employ the Environmental Exposure Unit (EEU) to conduct the first randomized controlled trial of PF-03654764 in allergic rhinitis. 64 participants were randomized in a double-blind, placebo-controlled 4-period crossover study. Participants were exposed to ragweed pollen for 6 hours post-dose in the EEU. The primary objective was to compare the effect of PF-03654764 + fexofenadine to pseudoephedrine + fexofenadine on the subjective measures of congestion and Total Nasal Symptom Score (TNSS). The objectives of our post-hoc analyses were to compare all treatments to placebo and determine the onset of action (OA). This trial was registered at ClinicalTrials.gov (NCT01033396). RESULTS: PF-03654764 + fexofenadine was not superior to pseudoephedrine + fexofenadine. In post-hoc analyses, PF-03654764 + fexofenadine significantly reduced TNSS, relative to placebo, and OA was 60 minutes. Pseudoephedrine + fexofenadine significantly reduced congestion and TNSS, relative to placebo, with OA of 60 and 30 minutes, respectively. Although this study was not powered for a statistical analysis of safety, it was noted that all PF-03654764-treated groups experienced an elevated incidence of adverse events. CONCLUSIONS: PF-03654764 + fexofenadine failed to provide superior relief of allergic rhinitis-associated nasal symptoms upon exposure to ragweed pollen compared to fexofenadine + pseudoephedrine. However, in post-hoc analyses, PF-03654764 + fexofenadine improved TNSS compared to placebo. Side effects in the PF-03654764-treated groups were clinically significant compared to the controls.

Effects of phthalates on the development and expression of allergic disease and asthma.

OBJECTIVE: To review recent evidence relating phthalate exposures to allergies and asthma and to provide an overview for clinicians interested in the relevance of environmental health research to allergy and who may encounter patients with concerns about phthalates from media reports. DATA SOURCES: PubMed, TOXLINE, and Web of Science were searched using the term phthalate(s) combined with the keywords allergy, asthma, atopy, and inflammation. STUDY SELECTIONS: Articles were selected based on relevance to the goals of this review. Studies that involved humans were prioritized, including routes and levels of exposure, developmental and early-life exposures, immunotoxicity, and the development of allergic disease. RESULTS: The general public and those with allergy are exposed to significant levels of phthalates via diet, pharmaceuticals, phthalate-containing products, and ambient indoor environment via air and dust. Intravenous exposures occur through medical equipment. Phthalates are metabolized and excreted quickly in the body with metabolites measured in urine. Phthalates, which are known endocrine disrupting compounds, have been associated with oxidative stress and alterations in cytokine expression. Metabolites in human urine, particularly of the higher-molecular-weight phthalates, have been associated with allergies and asthma in multiple studies. CONCLUSION: Despite mounting evidence implicating phthalates, causation of allergic disease by these compounds cannot currently be established. In utero and early-life exposures and possible transgenerational effects are not well understood. However, considering the current evidence, reducing exposures to phthalates by avoiding processed and foods packaged and stored in plastics, personal care products with phthalates, polyvinyl chloride materials indoors, and reducing home dust is advised. Further longitudinal, molecular, and intervention studies are needed to understand the association between phthalates and allergic disease.

Increased ornithine-derived polyamines cause airway hyperresponsiveness in a mouse model of asthma.

Up-regulation of arginase contributes to airways hyperresponsiveness (AHR) in asthma by reducing L-arginine bioavailability for the nitric oxide (NO) synthase isozymes. The product of arginase activity, L-ornithine, can be metabolized into polyamines by ornithine decarboxylase. We tested the hypothesis that increases in L-ornithine-derived polyamines contribute to AHR in mouse models of allergic airways inflammation. After measuring significantly increased polyamine levels in sputum samples from human subjects with asthma after allergen challenge, we used acute and subacute ovalbumin sensitization and challenge mouse models of allergic airways inflammation and naive mice to investigate the relationship of AHR to methacholine and polyamines in the lung. We found that spermine levels were elevated significantly in lungs from the acute model, which exhibits robust AHR, but not in the subacute murine model of asthma, which does not develop AHR. Intratracheal administration of spermine significantly augmented airways responsiveness to methacholine in both naive mice and mice with subacute airways inflammation, and reduced nitrite/nitrate levels in lung homogenates, suggesting that the AHR developed as a consequence of inhibition of constitutive NO production in the airways. Chronic inhibition of polyamine synthesis using an ornithine decarboxylase inhibitor significantly reduced polyamine levels, restored nitrite/nitrate levels to normal, and abrogated the AHR to methacholine in the acute model of allergic airways inflammation. We demonstrate that spermine increases airways responsiveness to methacholine, likely through inhibition of constitutive NO synthesis. Thus, inhibition of polyamine production may represent a new therapeutic target to treat airway obstruction in allergic asthma.

Spleen tyrosine kinase inhibition attenuates airway hyperresponsiveness and pollution-induced enhanced airway response in a chronic mouse model of asthma.

BACKGROUND: Asthma is a chronic inflammatory disease characterized by airways hyperresponsiveness (AHR), reversible airflow obstruction, airway remodeling, and episodic exacerbations caused by air pollutants, such as particulate matter (PM; PM <2.5 µm in diameter [PM(2.5)]) and ozone (O(3)). Spleen tyrosine kinase (Syk), an immunoregulatory kinase, has been implicated in the pathogenesis of asthma. OBJECTIVE: We sought to evaluate the effect of Syk inhibition on AHR in a chronic mouse model of allergic airways inflammation and pollutant exposure. METHODS: We used a 12-week chronic ovalbumin (OVA) sensitization and challenge mouse model of airways inflammation followed by exposure to PM(2.5) plus O(3). Respiratory mechanics and methacholine (MCh) responsiveness were assessed by using the flexiVent system. The Syk inhibitor NVP-QAB-205 was nebulized intratracheally by using a treatment-based protocol 15 minutes before assessment of MCh responsiveness. RESULTS: Syk expression increased significantly in the airway epithelia of OVA-sensitized and OVA-challenged (OVA/OVA) mice compared with OVA-sensitized but PBS-challenged (OVA/PBS) control mice. OVA/OVA mice exhibited AHR to MCh, which was attenuated by a single administration of NVP-QAB-205 (0.3 and 3 mg/kg). PM(2.5) plus O(3) significantly augmented AHR to MCh in the OVA/OVA mice, which was abrogated by NVP-QAB-205. Total inflammatory cell counts were significantly higher in the bronchoalveolar lavage fluid from OVA/OVA than OVA/PBS mice and were unaffected by PM(2.5) plus O(3) or NVP-QAB-205. CONCLUSION: NVP-QAB-205 reduced AHR and the enhanced response to PM(2.5) plus O(3) to normal levels in an established model of chronic allergic airways inflammation, suggesting that Syk inhibitors have promise as a therapy for asthma.

Comparative cardiopulmonary effects of size-fractionated airborne particulate matter.

CONTEXT: Strong epidemiological evidence exists linking particulate matter (PM) exposures with hospital admissions of individuals for cardiopulmonary symptoms. The PM size is important in influencing the extent of infiltration into the respiratory tract and systemic circulation and directs the differential physiological impacts. OBJECTIVE: To investigate the differential effects of the quasi-ultrafine (PM(0.2)), fine (PM(0.15-2.5)), and coarse PM (PM(2.5-10)) size fractions on pulmonary and cardiac function. METHODS: Female BALB/c mice were exposed to HEPA-filtered laboratory air or concentrated coarse, fine, or quasi-ultrafine PM using Harvard Ambient Particle Concentrators in conjunction with our nose-only exposure system. These exposures were conducted as part of the "Health Effects of Aerosols in Toronto (HEAT)" campaign. Following a 4 h exposure, mice underwent assessment of respiratory function and recording of electrocardiograms using the flexiVent® system. RESULTS: Exposure to coarse and fine PM resulted in a significant reduction in quasistatic compliance of the lung. Baseline total respiratory resistance and maximum responsiveness to methacholine were augmented after coarse PM exposures but were not affected by quasi-ultrafine PM exposures. In contrast, quasi-ultrafine PM alone had a significant effect on heart rate and in reducing heart rate variability. CONCLUSION: These findings indicate that coarse and fine PM influence lung function and airways responsiveness, while ultrafine PM can perturb cardiac function. This study supports the hypothesis that coarse and fine PM exerts its predominant physiologic effects at the site of deposition in the airways, whereas ultrafine PM likely crosses the alveolar epithelial barrier into the systemic circulation to affect cardiovascular function.

Hypertrophic airway smooth muscle mass correlates with increased airway responsiveness in a murine model of asthma.

The increase of airway smooth muscle (ASM) mass in asthma results from hypertrophic and hyperplastic stimuli, and leads to an increase in cellular contractile proteins. However, little evidence correlates the relative contributions of hypertrophic and hyperplastic muscle with functional effects on airway resistance. We performed a ventilator-based assessment of respiratory mechanics and responsiveness to methacholine in a murine model of acute (3-week) ovalbumin (OVA)-induced airway inflammation, compared with a chronic (12-week) model. We correlated functional changes in airways Newtonian resistance (RN), peripheral tissue damping (G), and elastance (H) with the relative contributions of proliferation, hypertrophy, and apoptosis to increased ASM mass. Immunohistochemical analyses of treated (OVA-sensitized and OVA-challenged; OVA/OVA) and control (OVA-sensitized and saline-challenged; OVA/PBS) murine lungs showed an increase in ASM area in chronic, but not acute, OVA/OVA-treated mice that correlated positively with increased airway resistance to methacholine. Acute OVA/OVA-treated ASM exhibited an increase in proliferation with diminished apoptosis, which resolved in the chronic OVA/OVA model. Chronic OVA/OVA-treated ASM exhibited hypertrophy. Distinct temporal differences exist in the response of murine airways to antigenic challenge. We report that ASM proliferation and diminished apoptosis occur during the acute phase, followed by the development of smooth muscle hypertrophy and an increased muscle mass with chronic challenge, that correlate strongly with increased airway Newtonian resistance. The identification of a functionally relevant hypertrophic bronchial muscle mass highlights the possibility of regulating airway muscle hypertrophy as a novel therapeutic target in asthma.

Asymmetric dimethylarginine is increased in asthma.

RATIONALE: Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase (NOS) inhibitor that competes with L-arginine for binding to NOS. It has been suggested that ADMA contributes to inflammation, collagen deposition, nitrosative stress, and lung function in murine models. OBJECTIVES: To test the hypothesis that ADMA is increased in asthma and that NOS inhibition by ADMA contributes to airways obstruction. METHODS: We assessed alterations of L-arginine, ADMA, and symmetric dimethylarginine (SDMA) levels in a murine model of allergic airways inflammation using LC-tandem mass spectrometry. Based on the levels of ADMA observed in the murine model, we further tested the direct effects of nebulized inhaled ADMA on airways responsiveness in naive control mice. We also assessed alterations of L-arginine, ADMA, and SDMA in humans in adult lung specimens and sputum samples from pediatric patients with asthma. MEASUREMENTS AND MAIN RESULTS: ADMA was increased in lungs from the murine model of allergic airways inflammation. Exogenous administration of ADMA to naive mice, at doses consistent with the levels observed in the allergically inflamed lungs, resulted in augmentation of the airways responsiveness to methacholine. ADMA levels were also increased in human asthma lungs and sputum samples. CONCLUSIONS: ADMA levels are increased in asthma and contribute to NOS-related pathophysiology.

The role of epigenetics in the developmental origins of allergic disease.

OBJECTIVE: To review current research findings in the field of epigenetics pertaining to the developmental origins of allergic disease. DATA SOURCES: We examined original research and review articles identified from MEDLINE, OVID, and PubMed that addressed the topic of interest, using the search terms atopy, allergy, asthma, development, IgE, origins, and cord blood paired with epigenetic(s). Relevant references from each article were also procured for review. STUDY SELECTION: Articles were selected based on their relevance to the contributory role of epigenetic modifications in asthma and other atopic diseases. RESULTS: There is increasing evidence pointing to the influence of prenatal and early life exposures on the development of allergic disease. A growing body of literature supports the theory that transient environmental pressures can have permanent effects on gene regulation and expression through epigenetic mechanisms. Histone modifications have been associated with degree of bronchial hyperresponsiveness and corticosteroid resistance in asthma. Epigenetic mechanisms can operate independently in various cell types; recent studies have suggested a role in the differentiation of human T cells. Murine studies have revealed that a maternal diet rich in methyl donors can enhance susceptibility to allergic inflammation in the offspring, mediated through increased DNA methylation. Murine studies have also implicated epigenetically modified dendritic cells in the transmission of allergic risk from mothers to offspring. CONCLUSION: The current literature offers exciting data to support a role for epigenetics in the development and persistence of asthma and allergic rhinitis. However, further human studies are necessary to explore these mechanisms and assess future clinical applicability.

Augmentation of arginase 1 expression by exposure to air pollution exacerbates the airways hyperresponsiveness in murine models of asthma.

BACKGROUND: Arginase overexpression contributes to airways hyperresponsiveness (AHR) in asthma. Arginase expression is further augmented in cigarette smoking asthmatics, suggesting that it may be upregulated by environmental pollution. Thus, we hypothesize that arginase contributes to the exacerbation of respiratory symptoms following exposure to air pollution, and that pharmacologic inhibition of arginase would abrogate the pollution-induced AHR. METHODS: To investigate the role of arginase in the air pollution-induced exacerbation of airways responsiveness, we employed two murine models of allergic airways inflammation. Mice were sensitized to ovalbumin (OVA) and challenged with nebulized PBS (OVA/PBS) or OVA (OVA/OVA) for three consecutive days (sub-acute model) or 12 weeks (chronic model), which exhibit inflammatory cell influx and remodeling/AHR, respectively. Twenty-four hours after the final challenge, mice were exposed to concentrated ambient fine particles plus ozone (CAP+O3), or HEPA-filtered air (FA), for 4 hours. After the CAP+O3 exposures, mice underwent tracheal cannulation and were treated with an aerosolized arginase inhibitor (S-boronoethyl-L-cysteine; BEC) or vehicle, immediately before determination of respiratory function and methacholine-responsiveness using the flexiVent®. Lungs were then collected for comparison of arginase activity, protein expression, and immunohistochemical localization. RESULTS: Compared to FA, arginase activity was significantly augmented in the lungs of CAP+O3-exposed OVA/OVA mice in both the sub-acute and chronic models. Western blotting and immunohistochemical staining revealed that the increased activity was due to arginase 1 expression in the area surrounding the airways in both models. Arginase inhibition significantly reduced the CAP+O3-induced increase in AHR in both models. CONCLUSIONS: This study demonstrates that arginase is upregulated following environmental exposures in murine models of asthma, and contributes to the pollution-induced exacerbation of airways responsiveness. Thus arginase may be a therapeutic target to protect susceptible populations against the adverse health effects of air pollution, such as fine particles and ozone, which are two of the major contributors to smog.

2-aminoimidazole amino acids as inhibitors of the binuclear manganese metalloenzyme human arginase I.

Arginase, a key metalloenzyme of the urea cycle that converts L-arginine into L-ornithine and urea, is presently considered a pharmaceutical target for the management of diseases associated with aberrant l-arginine homeostasis, such as asthma, cardiovascular diseases, and erectile dysfunction. We now report the design, synthesis, and evaluation of a series of 2-aminoimidazole amino acid inhibitors in which the 2-aminoimidazole moiety serves as a guanidine mimetic. These compounds represent a new class of arginase inhibitors. The most potent inhibitor identified in this study, 2-(S)-amino-5-(2-aminoimidazol-1-yl)pentanoic acid (A1P, 10), binds to human arginase I with K(d) = 2 microM and significantly attenuates airways hyperresponsiveness in a murine model of allergic airways inflammation. These findings suggest that 2-aminoimidazole amino acids represent new leads for the development of arginase inhibitors with promising pharmacological profiles.