The objective of the present study was to investigate exposure-response relationships between current endotoxin exposure and allergic and respiratory symptoms in adults, taking into account farming exposures during childhood.A cross-sectional study was conducted among 877 Dutch farmers and agricultural industry workers in 2006. Based on 249 full-shift personal airborne endotoxin samples, a job-exposure matrix was constructed to assign endotoxin exposure levels to all participants. Associations between endotoxin exposure and questionnaire data on symptoms were studied by multiple logistic regression.Adjusted odds ratios (OR) for an interquartile range increase in endotoxin level were elevated for respiratory symptoms such as wheezing (OR 1.41 (95% confidence interval 1.16-1.72)), wheezing with shortness of breath (1.50 (1.18-1.90)) and daily cough (1.29 (1.03-1.62)). In contrast, endotoxin was strongly associated with a decreased prevalence of hay fever (0.62 (0.49-0.78)). Workers who had grown up on a farm had a lower prevalence of hay fever, but no evidence was found of effect modification by farm childhood.In conclusion, occupational endotoxin exposure in adulthood is associated with an increased risk of asthma-like symptoms but a reduced prevalence of hay fever.

IntroductionSepsis-associated encephalopathy (SAE) is a state of acute brain dysfunction in response to a systemic infection. We propose that systemic inflammation during sepsis causes increased adhesion of leukocytes to the brain microvasculature, resulting in blood-brain barrier dysfunction. Thus, our objectives were to measure inflammatory analytes in plasma of severe sepsis patients to create an experimental cytokine mixture (CM), and to use this CM to investigate the activation and interactions of polymorphonuclear leukocytes (PMN) and human cerebrovascular endothelial cells (hCMEC/D3) in vitro.MethodsThe concentrations of 41 inflammatory analytes were quantified in plasma obtained from 20 severe sepsis patients and 20 age- and sex-matched healthy controls employing an antibody microarray. Two CMs were prepared to mimic severe sepsis (SSCM) and control (CCM), and these CMs were then used for PMN and hCMEC/D3 stimulation in vitro. PMN adhesion to hCMEC/D3 was assessed under conditions of flow (shear stress 0.7 dyn/cm2).ResultsEight inflammatory analytes elevated in plasma obtained from severe sepsis patients were used to prepare SSCM and CCM. Stimulation of PMN with SSCM led to a marked increase in PMN adhesion to hCMEC/D3, as compared to CCM. PMN adhesion was abolished with neutralizing antibodies to either β2 (CD18), αL/β2 (CD11α/CD18; LFA-1) or αM/β2 (CD11β/CD18; Mac-1) integrins. In addition, immune-neutralization of the endothelial (hCMEC/D3) cell adhesion molecule, ICAM-1 (CD54) also suppressed PMN adhesion.ConclusionsHuman SSCM up-regulates PMN pro-adhesive phenotype and promotes PMN adhesion to cerebrovascular endothelial cells through a β2-integrin-ICAM-1-dependent mechanism. PMN adhesion to the brain microvasculature may contribute to SAE.

Mechanisms of sepsis‐associated encephalopathy (SAE) are largely un‐investigated, however, impaired function of cerebrovascular endothelium has been suggested to play a key role. Our recent findings indicate that Severe Sepsis in humans results in up‐regulation of 13 out of 42 pro‐inflammatory cytokines/chemokines analyzed in blood plasma (e.g. IL‐6, MCP‐1, MIP‐1, IL‐8, IP‐10).In this study we used immortalized human‐derived cerebrovascular endothelial cells (hCVEC) to assess activation/dysfunction of hCVEC in response to stimulation with plasma (20% vol/vol) obtained from either patients with Severe Sepsis (hSSP) or healthy controls. Stimulation of hCVEC with hSSP for 1hr resulted in hCVEC activation as evidenced by increased ROS production (DHR123 oxidation). Subsequently, stimulation of hCVEC with hSSP resulted in increased PMN adhesion to hCVEC under conditions of flow (shear stress 1dyn/cm2) and increased hCVEC permeability as assessed by decreased transendothelial electric resistance. Interestingly, hSSP failed to induce activation of inflammation‐relevant transcription factor, NF‐κB (ELISA) following 1hr stimulation.In summary, our data indicate that pro‐inflammatory substance(s) present in human Severe Sepsis plasma induce activation/dysfunction of cerebrovascular endothelial cells, thus may contribute to the development of SAE (IRF 08‐10)

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