Cough responses to inhaled irritants are enhanced by eosinophil major basic protein in awake mice

A distinct association between airway eosinophilia and chronic cough is well documented. Eosinophil granule-derived cationic proteins, such as major basic protein (MBP), have been shown to activate and enhance the excitability of bronchopulmonary C-fiber sensory nerves, which may then lead to an increase in cough sensitivity. This study was carried out to determine whether cough responses to inhaled irritant gases were altered by delivery of MBP into the airways. An awake mouse moved freely in a recording chamber that was ventilated with a constant flow of air or irritant gas mixture. Cough responses to separate inhalation challenges of sulfur dioxide (SO2; 300 and 600 ppm) and ammonia (NH3; 0.1 and 0.2%), each for 5-min duration, were measured daily for 3 days before and for up to 8 days after MBP (10–20 µg) instillation into the trachea. During control, inhalations of SO2 and NH3 consistently elicited cough responses in a dose-dependent manner. After MBP treatment, cough responses to both SO2 and NH3 increased significantly and progressively and reached peaks 2–3 days after the treatment before returning to control level in 3–7 days. In sharp contrast, cough responses to these irritant gases were not affected by the treatment with the vehicle of MBP. These results suggest that the MBP-induced lingering elevation of cough responsiveness may be a contributing factor in the pathogenesis of chronic cough associated with eosinophilic infiltration of the airways.

Longitudinal changes in C-reactive protein, proform of eosinophil major basic protein, and pregnancy-associated plasma protein-A during weight changes in obese children

Childhood obesity is associated with several complications, including cardiovascular comorbidity. Several biomarkers, such as high-sensitive C-reactive protein (hs-CRP), proform of eosinophil major basic protein (Pro-MBP) and pregnancy associated plasma protein-A (PAPP-A), have equally been linked to increased cardiovascular susceptibility. This study investigates these biomarkers during weight loss and regain in obese children.A longitudinal study during a 12-week weight loss program with a 28 months follow-up was conducted. Anthropometrics and plasma concentrations of hs-CRP, Pro-MBP, and PAPP-A were measured at baseline; at days 14, 33 and 82 during weight loss; and at months 10, 16, and 28 during follow-up.Fifty-three boys and 62 girls aged 8–15 years with a median body mass index (BMI) standard deviation score (SDS) at baseline of 2.78 (boys), and 2.70 (girls) were included. Ninety children completed the weight loss program and 68 children entered the follow-up program. Pro-MBP and PAPP-A, but not hs-CRP, exhibited individual-specific levels (tracking) during weight loss and regain. The PAPP-A/Pro-MBP correlation was strong, whereas the hs-CRP/PAPP-A correlation was weak during weight fluctuations.Hs-CRP changes reflect weight changes. PAPP-A and Pro-MBP exhibited tracking during weight perturbations and may contribute as early risk markers of cardiovascular susceptibility.

Formation of high-molecular-weight angiotensinogen during pregnancy is a result of competing redox reactions with the proform of eosinophil major basic protein

The plasma concentration of the placentally derived proMBP (proform of eosinophil major basic protein) increases in pregnancy, and three different complexes containing proMBP have been isolated from pregnancy plasma and serum: a 2:2 complex with the metalloproteinase, PAPP-A (pregnancy-associated plasma protein-A), a 2:2 complex with AGT (angiotensinogen) and a 2:2:2 complex with AGT and complement C3dg. In the present study we show that during human pregnancy, all of the circulating proMBP exists in covalent complexes, bound to either PAPP-A or AGT. We also show that the proMBP–AGT complex constitutes the major fraction of circulating HMW (high-molecular weight) AGT in late pregnancy, and that this complex is able to further associate with complement C3 derivatives post-sampling. Clearance experiments in mice suggest that complement C3-based complexes are removed faster from the circulation compared to monomeric AGT and the proMBP–AGT complex. Furthermore, we have used recombinant proteins to analyse the formation of the proMBP–PAPP-A and the proMBP–AGT complexes, and we demonstrate that they are competing reactions, depending on the same cysteine residue of proMBP, but differentially on the redox potential, potentially important for the relative amounts of the complexes in vivo. These findings may be important physiologically, since the biochemical properties of the proteins change as a consequence of complex formation.