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Rationale: House endotoxin and ambient air pollution are risk factors for asthma; however, the effects of their coexposure on asthma are not well characterized. Objectives: To examine potential synergistic associations of coexposure to house dust endotoxin and ambient air pollutants with asthma outcomes. Methods: We analyzed data of 6,488 participants in the National Health and Nutrition Examination Survey 2005–2006. Dust from bedding and bedroom floor was analyzed for endotoxin content. The Community Multiscale Air Quality Modeling System (CMAQ) and Downscaler Model data were used to determine annual average particulate matter ≤2.5 μm in aerodynamic diameter (PM(2.5)), ozone (O(3)), and nitrogen dioxide (NO(2)) exposures at participants’ residential locations. The associations of the coexposures with asthma outcomes were assessed and tested for synergistic interaction. Measurements and Main Results: In adjusted analysis, PM(2.5) (CMAQ) (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.07–1.18), O(3) (Downscaler Model) (OR, 1.07; 95% CI, 1.02–1.13), and log(10) NO(2) (CMAQ) (OR, 3.15; 95% CI, 1.33–7.45) were positively associated with emergency room visits for asthma in the past 12 months. Coexposure to elevated concentrations of house dust endotoxin and PM(2.5) (CMAQ) was synergistically associated with the outcome, increasing the odds by fivefold (OR, 5.01; 95% CI, 2.54–9.87). A synergistic association was also found for coexposure to higher concentrations of endotoxin and NO(2) in children (OR, 3.45; 95% CI, 1.65–7.18). Conclusions: Coexposure to elevated concentrations of residential endotoxin and ambient PM(2.5) in all participants and NO(2) in children is synergistically associated with increased emergency room visits for asthma. Therefore, decreasing exposure to both endotoxin and air pollution may help reduce asthma morbidity.

Regions of diminished ventilation are often evident during functional pulmonary imaging studies, including hyperpolarized gas magnetic resonance imaging (MRI), positron emission tomography, and computed tomography (CT). The objective of this study was to characterize the hypointense regions observed via (3)He MRI in a murine model of acute lung injury. LPS at doses ranging from 15-50 μg was intratracheally administered to C57BL/6 mice under anesthesia. Four hours after exposure to either LPS or saline vehicle, mice were imaged via hyperpolarized (3)He MRI. All images were evaluated to identify regions of hypointense signals. Lungs were then characterized by conventional histology, or used to obtain tissue samples from regions of normal and hypointense (3)He signals and analyzed for cytokine content. The characterization of (3)He MRI images identified three distinct types of hypointense patterns: persistent defects, atelectatic defects, and dorsal lucencies. Persistent defects were associated with the administration of LPS. The number of persistent defects depended on the dose of LPS, with a significant increase in mean number of defects in 30-50-μg LPS-dosed mice versus saline-treated control mice. Atelectatic defects predominated in LPS-dosed mice under conditions of low-volume ventilation, and could be reversed with deep inspiration. Dorsal lucencies were present in nearly all mice studied, regardless of the experimental conditions, including control animals that did not receive LPS. A comparison of (3)He MRI with histopathology did not identify tissue abnormalities in regions of low (3)He signal, with the exception of a single region of atelectasis in one mouse. Furthermore, no statistically significant differences were evident in concentrations of IL-1β, IL-6, macrophage inflammatory protein (MIP)-1α, MIP-2, chemokine (C-X-C motif) ligand 1 (KC), TNFα, and monocyte chemotactic protein (MCP)-1 between hypointense and normally ventilated lung regions in LPS-dosed mice. Thus, this study defines the anatomic, functional, and biochemical characteristics of ventilation defects associated with the administration of LPS in a murine model of acute lung injury.

Pulmonary arterial hypertension (PAH) is a life-threatening disease that leads to progressive pulmonary hypertension, right heart failure, and death. Endothelial dysfunction and inflammation were implicated in the pathogenesis of PAH. Epoxyeicosatrienoic acids (EETs), products of the cytochrome P450 epoxygenase metabolism of arachidonic acid, are potent vasodilators that possess anti-inflammatory and other protective properties in endothelial cells. We investigated whether gene delivery with the human cytochrome P450 epoxygenase 2J2 (CYP2J2) ameliorates monocrotaline (MCT)-induced pulmonary hypertension in rats. Significant pulmonary hypertension developed 3 weeks after the administration of MCT, but gene therapy with CYP2J2 significantly attenuated the development of pulmonary hypertension and pulmonary vascular remodeling, without causing changes in systemic arterial pressure or heart rate. These effects were associated with increased pulmonary endothelial NO synthase (eNOS) expression and its activity, inhibition of inflammation in the lungs, and transforming growth factor (TGF)-β/type II bone morphogenetic protein receptor (BMPRII)-drosophila mothers against decapentaplegic proteins (Smads) signaling. Collectively, these data suggest that gene therapy with CYP2J2 may have potential as a novel therapeutic approach to this progressive and oftentimes lethal disorder.

Numerous studies in humans and experimental animals have identified considerable sex differences in respiratory physiology and in the response of the lung to environmental agents. These differences appear to be mediated, at least in part, by sex hormones and their nuclear receptors. Moreover, animal models are increasingly used to study pathogenic mechanisms and test potential therapies for a variety of human lung diseases, many of which appear to be influenced by sex and sex hormones. In this article, data are summarized from studies of lung function and disease in which sex differences have been observed. Specific attention is paid to animal models of acute lung injury, nonallergic and allergic lung inflammation, and lung fibrosis. It is anticipated that continued investigation of the role of sex and sex hormones in animal models will provide valuable insight into the pathogenesis and potential treatments for a variety of acute and chronic human lung diseases.

The roles of sex hormones as modulators of lung function and disease have received significant attention as differential sex responses to various lung insults have been recently reported. The present study used a bleomycin-induced pulmonary fibrosis model in C57BL/6 mice to examine potential sex differences in physiological and pathological outcomes. Endpoints measured included invasive lung function assessment, immunological response, lung collagen deposition, and a quantitative histological analysis of pulmonary fibrosis. Male mice had significantly higher basal static lung compliance than female mice (P < 0.05) and a more pronounced decline in static compliance after bleomycin administration when expressed as overall change or percentage of baseline change (P < 0.05). In contrast, there were no significant differences between the sexes in immune cell infiltration into the lung or in total lung collagen content after bleomycin. Total lung histopathology scores measured using the Ashcroft method did not differ between the sexes, while a quantitative histopathology scoring system designed to determine where within the lung the fibrosis occurred indicated a tendency toward more fibrosis immediately adjacent to airways in bleomycin-treated male versus female mice. Furthermore, castrated male mice exhibited a female-like response to bleomycin while female mice given exogenous androgen exhibited a male-like response. These data indicate that androgens play an exacerbating role in decreased lung function after bleomycin administration, and traditional measures of fibrosis may miss critical differences in lung function between the sexes. Sex differences should be carefully considered when designing and interpreting experimental models of pulmonary fibrosis in mice.

Acute pharmacologic inhibition of cyclooxygenase (COX)-1 or -2 during allergen sensitization and exposure leads to enhanced T helper type 2 (Th2) airway responses. COX-1 and -2 play functionally distinct roles in lymphocyte development, and consequently, genetic deficiency of either enzyme, as opposed to acute pharmacologic inhibition, may modulate Th2-mediated allergic airway disease differently. An ovalbumin-induced mouse model of allergic airway disease was used. The immunophenotype of bronchoalveolar lavage lymphocytes was assessed by flow cytometry, bronchoalveolar lavage cytokines, and chemokines were measured by enzyme-linked immunosorbent assay, adhesion molecule expression was assessed by immunoblotting in combination with immunohistochemistry, and bronchoconstriction was assessed by whole body plethysmography. The airways of COX-1-/- mice contained increased numbers of CD4+ and CD8+ T cells, exaggerated levels of the Th2 cytokines interleukin-4, -5, and -13, and increased levels of eotaxin and thymus- and activation-regulated chemokine. Allergen-induced bronchoconstriction was also increased in COX-1-/- mice. Vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 levels were increased in lungs of both COX-1-/- and COX-2-/- mice relative to wild type. These data suggest that genetic deficiency of COX-1 but not COX-2 modulates T cell recruitment, Th2 cytokine secretion, and lung function in the allergic airway.

Th17 cells comprise a distinct lineage of proinflammatory T helper cells that are major contributors to allergic responses. It is unknown whether cyclooxygenase (COX)-derived eicosanoids regulate Th17 cells during allergic lung inflammation.To determine the role of COX metabolites in regulating Th17 cell differentiation and function during allergic lung inflammation.COX-1(-/-), COX-2(-/-), and wild-type mice were studied in an in vivo model of ovalbumin-induced allergic inflammation and an in vitro model of Th17 differentiation using flow cytometry, cytokine assays, confocal microscopy, real-time polymerase chain reaction, and immunoblotting. In addition, the role of specific eicosanoids and their receptors was examined using synthetic prostaglandins (PGs), selective inhibitors, and siRNA knockdown.Th17 cell differentiation in lung, lymph nodes, and bronchoalveolar lavage fluid was significantly lower in COX-2(-/-) mice after ovalbumin sensitization and exposure in vivo. In vitro studies revealed significantly impaired Th17 cell differentiation of COX-2(-/-) naive CD4(+) T cells with decreased Stat3 phosphorylation and RORγt expression. Synthetic PGF(2α) and PGI(2) enhanced Th17 cell differentiation of COX-2(-/-) CD4(+) T cells in vitro. The selective COX-2 inhibitor, NS-398, and PGF(2α) receptor and PGI(2) receptor siRNA knockdown significantly decreased Th17 cell differentiation in vitro. Administration of synthetic PGs restored accumulation of Th17 cells in lungs of allergic COX-2(-/-) mice in vivo.COX-2 is a critical regulator of Th17 cell differentiation during allergic lung inflammation via autocrine signaling of PGI(2) and PGF(2α) through their respective cell surface receptors.

Although research has shown that early life exposure to household endotoxin protects against development of allergies, studies are less clear on the relationship between household endotoxin exposure and prevalence of wheezing and asthma. We assayed 2,552 house dust samples in a representative nationwide sam- ple to explore relationships between endotoxin exposures and risk factors for asthma, asthma symptoms, and medication use.House dust was vacuum-sampled from five locations within homes and assayed for endotoxin. Health, demographic, and housing information was assessed through questionnaire and on-site evaluation of 2,456 residents of 831 homes selected to represent the demographics of the United States.Endotoxin concentration (EU/mg) and load (EU/m(2)) were highly correlated (r = 0.73-0.79). Geometric mean endotoxin concentrations were as follows (in EU/mg): bedroom floors, 35.3 (5th-95th percentile, 5.0-260); bedding, 18.7 (2.0-142); family room floors, 63.9 (11.5-331); sofas, 44.8 (6.4-240); and kitchen floors, 80.5 (9.8-512). Multivariate analysis demonstrated significant relationships between increasing endotoxin levels and diagnosed asthma, asthma symptoms in the past year, current use of asthma medications, and wheezing among residents of the homes. These relationships were strongest for bedroom floor and bedding dust and were observed in adults only. Modeling the joint effect of bedding and bedroom floor endotoxin on recent asthma symptoms yielded an adjusted odds ratio of 2.83 (95% confidence interval, 1.01-7.87). When stratified by allergy status, allergic subjects with higher endotoxin exposure were no more likely to have diagnosed asthma or asthma symptoms than nonallergic subjects.This study demonstrates that household endotoxin exposure is a significant risk factor for increased asthma prevalence.

In their recent study on endotoxin exposure as a risk factor for asthma, Thorne and colleagues found a relation between floor dust endotoxin levels and diagnosed asthma, asthmamedication, and wheezing among adults (1). While I agree with the authors’ conclusion that the symptomatology reflects an inflammatory response that is more pronounced among those with an allergy, I would caution against any conclusions concerning causality. In house dust, endotoxin is only one of many microbial cell wall agents (MCWAs) with biological effects; other examples are mycobacterial lipoglycans, lipoteichoic acid, peptidoglycan, N-acetylmuramic acid, and lipoarabinomannan (2). Many MCWAs have inflammatory properties. Although the MCWA (1-3)-D-glucan is not inflammatory by itself (3), it reflects the presence of mold cells, which cause a neutrophilic inflammation akin to endotoxin. Previous reports have shown a significant correlation between levels of airborne endotoxin and (1-3)-D-glucan (4). So while we all would like to see a specific agent as the reason for effects found, the environment seldom provides this opportunity. From a practical point of view, however, endotoxin is useful as a marker for risk, and a reduction of these levels, particularly in occupational settings, will reduce the risk, whether this is related to endotoxin or some other covarying agent.