Chronic Obstructive Pulmonary Disease Patients Have Greater Systemic Responsiveness to Ex Vivo Stimulation with Swine Dust Extract and its Components Versus Healthy Volunteers

Chronic obstructive pulmonary disease (COPD) is characterized by an airway and systemic inflammatory response. Bioaerosols/organic dusts are important agricultural pollutants that may lead to COPD. These environments are complex containing a rich source of various microbial components. The objective of this study was to determine whether individuals with COPD have enhanced systemic responsiveness to settled swine facility organic dust extract (ODE) or its main pathogenic components (peptidoglycan [PGN], lipopolysaccharide [LPS]) versus healthy volunteers. A modified whole blood assay (WBA) that included occupational levels of ODE and concentrations of LPS and PGN found in ODE was used to determine systemic responsiveness (mediator release), and sputum inflammatory markers were measured to explore for systemic and airway associations. Sputum samples were evaluated for cell counts, and TNF-α, IL-8/CXCL8, IL-6, and IL-10. Ex vivo whole blood stimulation with ODE, LPS, and PGN each resulted in significant mediator release in all subjects, the highest occurring with ODE; PGN resulted in significantly enhanced TNF-α and IL-8 as compared to LPS. COPD subjects demonstrated greater systemic responsiveness using the modified WBA versus healthy controls. Within COPD subjects, blood baseline TNF-α, IL-8, and IL-10 and ODE, PGN, and LPS-stimulated IL-8 levels significantly correlated with lung function. In conclusion, dust-induced mediator release was robust, and PGN, in part, resembled dust-induced mediator release. Subjects with COPD demonstrated increased mediator release following ex vivo whole blood stimulation with bioaerosol components suggesting that circulating blood cells in COPD subjects may be primed to respond greater to microbial/inflammatory insult

Authors' response to comments from Nachman KE et al.

Abstract Authors’ response to comments letter to the editor from Nachman KE et al

Updated systematic review:Associations between proximity to animal feeding operations and health of individuals in nearby communities

Abstract Objective The objective of this review was to update a systematic review of associations between living near an animal feeding operation (AFO) and human health. Methods The MEDLINE® and MEDLINE® In-Process, Centre for Agricultural Biosciences Abstracts, and Science Citation Index databases were searched. Reference lists of included articles were hand-searched. Eligible studies reported exposure to an AFO and an individual-level human health outcome. Two reviewers performed study selection and data extraction. Results The search returned 3702 citations. Sixteen articles consisting of 10 study populations were included in the analysis. The health outcomes were lower and upper respiratory tracts, MRSA, other infectious disease, neurological, psychological, dermatological, otologic, ocular, gastrointestinal, stress and mood, and other non-infectious health outcomes. Most studies were observational and used prevalence measures of outcome. An association between Q fever risk and proximity to goat production was reported. Other associations were unclear. Risk of bias was serious or critical for most exposure-outcome associations. Multiplicity (i.e., a large number of potentially correlated outcomes and exposures assessed on the same study subjects) was common in the evidence base. Conclusions Few studies reported an association between surrogate clinical outcomes and AFO proximity for respiratory tract-related outcomes. There were no consistent dose-response relationships between surrogate clinical outcome and AFO proximity. A new finding was that Q fever in goats is likely associated with an increased Q fever risk in community members. The review results for the non-respiratory health outcomes were inconclusive because only a small number of studies were available or the between-study results were inconsistent. Systematic review registration PROSPERO CRD4201401052

Repeat Organic Dust Exposure–Induced Monocyte Inflammation is Associated with Protein Kinase C Activity

Background: Organic dust exposure results in an inflammatory response that attenuates over time, but repetitive exposures can result in chronic respiratory diseases. Mechanisms underlying this modulated response are not clear. Objective: This study investigated the effects of repeat versus single organic dust exposure–induced inflammatory mediators and protein kinase C (PKC) activity in monocytes. Methods: Settled organic dust was obtained from swine confinement facilities. Promonocytic THP-1 cells and human peripheral blood monocytes were pretreated with or without dust extract and then restimulated. Culture supernatants were evaluated for TNF-α, IL-6, CXCL8, and IL-10. Responses were compared with endotoxin-depleted dust, LPS, and peptidoglycan. PKC isoform (α, δ, ε, ζ) activation was evaluated by direct kinase activity. PKC isoform inhibitors’ effects on TNF-a secretion were studied. Results: Single exposure to organic dust stimulated monocyte secretion of TNF-α, IL-6, CXCL8, and IL-10 compared with unstimulated cells. TNF-α and IL-6 were diminished in pretreated cells restimulated with dust. Secretion of CXCL8 and IL-10 remained persistently elevated. TNF-α responses were retained after marked depletion of endotoxin. Dust exposure induced significant PKC α, δ, ε, and ζ activation, peaking at 30 to 60 minutes. PKC isoform activation was attenuated in repeat exposed cells. Inhibition of PKCa and PKCe reduced dust-induced TNF-α secretion. Conclusion: Repeat organic dust exposure modulated inflammatory mediator production in monocytes independent of endotoxin. The inability of PKC to be reactivated may account for this observation. Clinical implications: Targeting PKC and specific mediators associated with repetitive organic dust exposure may result in novel therapeutic strategies

Intranasal organic dust exposure-induced airway adaptation response marked by persistent lung inflammation and pathology in mice

Organic dust exposure in agricultural environments results in an inflammatory response that attenuates over time, but repetitive exposures can result in chronic respiratory disease. Animal models to study these mechanisms are limited. This study investigated the effects of single vs. repetitive dust-induced airway inflammation in mice by intranasal exposure method. Mice were exposed to swine facility dust extract (DE) or saline once and once daily for 1 and 2 wk. Dust exposure resulted in increased bronchoalveolar lavage fluid neutrophils and macrophages after single and repetitive exposures. Lavage fluid TNFα, IL-6, keratinocyte chemoattractant, and macrophage inflammatory protein-2 were significantly increased after single and repetitive dust exposures, but were dampened in 2-wk dust-exposed mice compared with single exposure. Dust exposure induced PKCα and -ɛ activation in isolated tracheal epithelial cells but were dampened with repetitive exposures. Ex vivo stimulation of alveolar macrophages from 2-wk animals demonstrated reduced cytokine responsiveness and phagocytic ability. Significant lung pathology occurred with development of mixed mononuclear cellular aggregates (T and B lymphocytes, phagocytes) after repetitive dust exposure, a novel observation. Airway hyperresponsiveness to methacholine occurred after single dust exposure but resolved after 2 wk. Collectively, intranasal exposure to DE results in significant lung inflammatory and pathological responses marked by a modulated innate immune response to single and repetitive dust exposures that is associated with PKC activity