Search

Abstract Numerous studies have shown that air pollutants, including diesel exhaust (DE), reduce host defenses, resulting in decreased resistance to respiratory infections. This study sought to determine if DE exposure could affect the severity of an ongoing influenza infection in mice, and examine if this could be modulated with antioxidants. BALB/c mice were treated by oropharyngeal aspiration with 50 plaque forming units of influenza A/HongKong/8/68 and immediately exposed to air or 0.5 mg/m3 DE (4 hrs/day, 14 days). Mice were necropsied on days 1, 4, 8 and 14 post-infection and lungs were assessed for virus titers, lung inflammation, immune cytokine expression and pulmonary responsiveness (PR) to inhaled methacholine. Exposure to DE during the course of infection caused an increase in viral titers at days 4 and 8 post-infection, which was associated with increased neutrophils and protein in the BAL, and an early increase in PR. Increased virus load was not caused by decreased interferon levels, since IFN-β levels were enhanced in these mice. Expression and production of IL-4 was significantly increased on day 1 and 4 p.i. while expression of the Th1 cytokines, IFN-γ and IL-12p40 was decreased. Treatment with the antioxidant N-acetylcysteine did not affect diesel-enhanced virus titers but blocked the DE-induced changes in cytokine profiles and lung inflammation. We conclude that exposure to DE during an influenza infection polarizes the local immune responses to an IL-4 dominated profile in association with increased viral disease, and some aspects of this effect can be reversed with antioxidants.

Introduction: Increases in ambient levels of ozone (O 3 ), a criteria air pollutant, have been associated with increased susceptibility and exacerbations of chronic pulmonary diseases through lung injury and inflammation. O 3 induces pulmonary inflammation, in part by generating damage-associated molecular patterns (DAMPs), which are recognized by pattern recognition receptors (PRRs), such as toll-like receptors (TLRs) and scavenger receptors (SRs). This inflammatory response is mediated in part by alveolar macrophages (AMs), which highly express PRRs, including scavenger receptor BI (SR-BI). Once pulmonary inflammation has been induced, an active process of resolution occurs in order to prevent secondary necrosis and to restore tissue homeostasis. The processes known to promote the resolution of inflammation include the clearance by macrophages of apoptotic cells, known as efferocytosis, and the production of specialized pro-resolving mediators (SPMs). Impaired efferocytosis and production of SPMs have been associated with the pathogenesis of chronic lung diseases; however, these impairments have yet to be linked with exposure to air pollutants., Specific Aims: The primary goals of this study were: Aim 1 - to define the role of SR-BI in O 3 -derived pulmonary inflammation and resolution of injury; and Aim 2 - to determine if O 3 exposure alters pulmonary production of SPMs and processes known to promote the resolution of pulmonary inflammation and injury., Methods: To address Aim 1, female wild-type (WT) and SR-BI-deficient, or knock-out (SR-BI KO), mice were exposed to either O 3 or filtered air. In one set of experiments mice were instilled with an oxidized phospholipid (oxPL). Bronchoalveolar lavage fluid (BALF) and lung tissue were collected for the analyses of inflammatory and injury markers and oxPL. To estimate efferocytosis, mice were administered apoptotic cells (derived from the Jurkat T cell line) after O 3 or filtered air exposure., To address Aim 2, male WT mice were exposed to either O 3 or filtered air, and levels of SPMs were assessed in the lung, as well as markers of inflammation and injury in BALF. In some experiments SPMs were administered before exposure to O 3 or filtered air, to determine whether SPMs could mitigate inflammatory or resolution responses. Efferocytosis was measured as in Aim 1., Results: For Aim 1, SR-BI protein levels increased in the lung tissue of mice exposed to O 3 , compared with mice exposed to filtered air. Compared with WT controls, SR-BI KO mice had a significant increase in the number of neutrophils in their airspace 24 hours post O 3 exposure. The oxPL levels increased in the airspace of both WT and SR-BI KO mice after O 3 exposure, compared with filtered air controls. Four hours after instillation of an oxPL, SR-BI KO mice had an increase in BALF neutrophils and total protein, and a nonsignificant increase in macrophages compared with WT controls. O 3 exposure decreased efferocytosis in both WT and SR-BI KO female mice., For Aim 2, mice given SPM supplementation before O 3 exposure showed significantly increased AM efferocytosis when compared with the O 3 exposure control mice and also showed some mitigation of the effects of O 3 on inflammation and injury. Several SPMs and their precursors were measured in lung tissue using reverse-phase high performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS). At 24 hours after O 3 exposure 14R-hydroxydocosahexaenoic acid (HDHA) and 10,17-dihydroxydocosahexaenoic acid (diHDoHE) were significantly decreased in lung tissue, but at 6 hours after exposure, levels of these SPMs increased., Conclusions: Our findings identify novel mechanisms by which O 3 may induce pulmonary inflammation and also increase susceptibility to and exacerbations of chronic lung diseases., (© 2021 Health Effects Institute. All rights reserved.)

In December 2016, the Wisconsin Department of Health Services (WDHS) notified CDC of a patient hospitalized with fever, leukopenia, elevated transaminases, and proteinuria. The patient owned and operated an in-home rattery, or rat-breeding facility, with approximately 100 Norway rats, primarily bred as pets. A family member developed similar symptoms 4 weeks later, but was not hospitalized. Because both patients were known to have rodent contact, they were tested for hantavirus infections. In January 2017, CDC confirmed recent, acute Seoul virus infection in both patients. An investigation was conducted to identify additional human and rat infections and prevent further transmission. Ultimately, the investigation identified 31 facilities in 11 states with human and/or rat Seoul virus infections; six facilities also reported exchanging rats with Canadian ratteries. Testing of serum samples from 183 persons in the United States and Canada identified 24 (13.1%) with Seoul virus antibodies; three (12.5%) were hospitalized and no deaths occurred. This investigation, including cases described in a previously published report from Tennessee (1), identified the first known transmission of Seoul virus from pet rats to humans in the United States and Canada. Pet rat owners should practice safe rodent handling to prevent Seoul virus infection (2)., Competing Interests: No conflicts of interest were reported.

Obesity is associated with increased risk for infections and poor responses to vaccinations, which may be due to compromised B cell function. However, there is limited information about the influence of obesity on B cell function and underlying factors that modulate B cell responses. Therefore, we studied B cell cytokine secretion and/or Ab production across obesity models. In obese humans, B cell IL-6 secretion was lowered and IgM levels were elevated upon ex vivo anti-BCR/TLR9 stimulation. In murine obesity induced by a high fat diet, ex vivo IgM and IgG were elevated with unstimulated B cells. Furthermore, the high fat diet lowered bone marrow B cell frequency accompanied by diminished transcripts of early lymphoid commitment markers. Murine B cell responses were subsequently investigated upon influenza A/Puerto Rico/8/34 infection using a Western diet model in the absence or presence of docosahexaenoic acid (DHA). DHA, an essential fatty acid with immunomodulatory properties, was tested because its plasma levels are lowered in obesity. Relative to controls, mice consuming the Western diet had diminished Ab titers whereas the Western diet plus DHA improved titers. Mechanistically, DHA did not directly target B cells to elevate Ab levels. Instead, DHA increased the concentration of the downstream specialized proresolving lipid mediators (SPMs) 14-hydroxydocosahexaenoic acid, 17-hydroxydocosahexaenoic acid, and protectin DX. All three SPMs were found to be effective in elevating murine Ab levels upon influenza infection. Collectively, the results demonstrate that B cell responses are impaired across human and mouse obesity models and show that essential fatty acid status is a factor influencing humoral immunity, potentially through an SPM-mediated mechanism., (Copyright © 2017 by The American Association of Immunologists, Inc.)

TCR signaling plays a critical role in regulatory T cell (Treg) development. However, the mechanism for tissue-specific induction of Tregs in the periphery remains unclear. We observed that surfactant protein A (SP-A)-deficient mice have impaired expression of Foxp3 and fewer CD25(+)Foxp3(+) Tregs after ex vivo stimulation and after stimulation with LPS in vivo. The addition of exogenous SP-A completely reversed this phenotype. Although SP-A is known to inhibit T cell proliferation under certain activation conditions, both IL-2 levels as well as active TGF-β levels increase on extended culture with exogenous SP-A, providing a key mechanism for the maintenance and induction of Tregs. In addition, kinetic suppression assays demonstrate that SP-A enhances the frequency of functional Foxp3(+) Tregs in responder T cell populations in a TGF-β-dependent manner. In mice treated with LPS in vivo, Tregs increased ∼160% in wild-type mice compared with only a 50% increase in LPS-treated SP-A(-/-) mice 8 d after exposure. Taken together, these findings support the hypothesis that SP-A affects T cell immune function by the induction of Tregs during activation.

We have previously shown that exposure of respiratory epithelial cells to diesel exhaust (DE) enhances susceptibility to influenza infection and increases the production of interleukin (IL)-6 and interferon (IFN)-beta. The purpose of this study was to confirm and expand upon these in vitro results by assessing the effects of DE exposure on the progression of influenza infection and on development of associated pulmonary immune and inflammatory responses in vivo. BALB/c mice were exposed to air or to DE containing particulate matter at concentrations of 0.5 or 2 mg/m(3) for 4 h/day for 5 days and subsequently instilled with influenza A/Bangkok/1/79 virus. Exposure to 0.5 mg/m(3) (but not the higher 2-mg/m(3) dose) of DE increased susceptibility to influenza infection as demonstrated by a significant increase in hemagglutinin (HA) mRNA levels, a marker of influenza copies, and greater immunohistochemical staining for influenza virus protein in the lung. The enhanced susceptibility to infection observed in mice exposed to 0.5 mg/m(3) of DE was associated with a significant increase in the expression of IL-6, while antiviral lung IFN levels were unaffected. Analysis of the expression and production of surfactant proteins A and D, which are components of the interferon-independent antiviral defenses, showed that these factors were decreased following exposure to 0.5 mg/m(3) of DE but not to the higher 2-mg/m(3) concentration. Taken together, the results demonstrate that exposure to DE enhances the susceptibility to respiratory viral infections by reducing the expression and production of antimicrobial surfactant proteins.