We report a 68 yr old woman with hypertension who developed a dry cough on enalapril but not on captopril therapy. Pulmonary function tests, methacholine inhalation challenges, total blood eosinophil counts, and changes in plasma concentrations of prostaglandin E2 and thromboxane B2 did not explain the difference in the adverse reaction between these two angiotensin converting enzyme inhibitors.

Background Dysbiotic intestinal and oral microbiota have been implicated in the pathogenesis of rheumatoid arthritis (RA), but the mechanisms how microbiota could impact disease activity have remained elusive. The aim of this study was to assess the association of the biological activity of serum lipopolysaccharides (LPS) with disease activity and likelihood of achieving remission in RA patients. Methods We measured Toll-like receptor (TLR) 4-stimulating activity of sera of 58 RA patients with a reporter cell line engineered to produce secreted alkaline phosphatase in response to TLR4 stimulation. Levels of LPS-binding protein, CD14, and CD163 were determined by ELISA assays. Results The patient serum-induced TLR4 activation (biological activity of LPS) was significantly associated with inflammatory parameters and body mass index at baseline and at 12 months and with disease activity (DAS28-CRP, p<0.001) at 12 months. Importantly, baseline LPS bioactivity correlated with disease activity (p=0.031) and, in 28 early RA patients, the likelihood of achieving remission at 12 months (p=0.009). The level of LPS bioactivity was similar at baseline and 12-month visits, suggesting that LPS bioactivity is an independent patient-related factor. Neutralization of LPS in serum by polymyxin B abrogated the TLR4 signaling, suggesting that LPS was the major contributor to TLR4 activation. Conclusion We describe a novel approach to study the biological activity of serum LPS and their impact in diseases. The results suggest that LPS contribute to the inflammatory burden and disease activity on patients with RA and that serum-induced TLR4 activation assays can serve as an independent prognostic factor. Graphical Abstract A graphical summary of the conclusions of the study.

1 We studied the ability of inhaled budesonide to modulate PAF-induced acute effects in nine healthy nonsmoking volunteers. Responses in inflammatory cells and mediators in peripheral blood as well as in pulmonary function and circulation were monitored.2 Inhalation of increasing doses of PAF (total cumulative dose of 500 Pg) caused a rapid and profound decrease in circulating white blood cells, especially in granulocytes (P < 0.01), which was turned to an increased number of these cells (P < 0.05, P < 0.025, respectively) in the blood samples taken 8 min after completion of the PAF challenge.No changes in the circulating platelets or their thromboxane production were found. Plasma concentrations of histamine or methylhistamine remained unchanged during PAF-inhalation, while plasma LTB4 tripled from the baseline level at 10 min (P < 0.0005) and was returned to the pre-PAF value at 60 min. 3 PAF inhalation induced a bronchial obstruction (P < 0.025), but no bronchial hyperresponsiveness to methacholine was found in any of our subjects when measured 24 h after the PAF challenge. Furthermore, PAF caused a decrease in systolic blood pressure (P < 0.05). 4 Budesonide pretreatment of 400 ,ug twice daily during the preceding 5 days had no effect on any PAF-induced events measured in our study. That fact may also contradict the role of bronchial resident or alveolar cells as a source of the PAFinduced LTB4 burst in plasma. 5 We conclude that in healthy volunteers inhaled PAF induces a marked increase in plasma LTB4, which is not inhibited by inhaled budesonide. We suggest that LTB4 originates from the circulating neutrophils activated in the bronchial capillary net by inhaled PAF. The failing plasma histamine response during PAF provocation contradicts a main role of this mediator in PAF-induced bronchial obstruction or circulatory events.