The role of C1 inhibitor and complement as acute phase reactants: are we missing the diagnosis of hereditary angioedema?

BACKGROUND: C1 inhibitor (C1-INH) and complement 4 (C4) have historically been referred to as positive acute phase reactants, however this has never been evaluated in hereditary angioedema (HAE) patients. Low function of C1-INH and low levels of C4 are important in the diagnosis of HAE type 1 and 2. If C1-INH and/or C4 are significant acute phase reactants, their levels may be falsely "normal" in patients with HAE when measured during times of infection or inflammation resulting in missed or delayed diagnosis. CASE PRESENTATION: We present a case series of four HAE patients who had C4, C1-INH, c-reactive protein (CRP) and ferritin measured at baseline and again during a self-reported upper respiratory tract infection (URTI) or flu-like illness. We did not identify any HAE patients who had a significant change in their C1-INH functional level in the context of a mild infection. However, the C4 level did increase into the normal range on three occasions (2 patients, with 1 patient having elevation during two separate illnesses). CONCLUSIONS: C1 inhibitor may not be a clinically significant acute phase protein and appears to still be a reliable diagnostic marker of hereditary angioedema, even in times of modest acute inflammation, unlike complement C4 which can be elevated in this setting.

Developments in asthma incidence and prevalence in Alberta between 1995 and 2015.

BACKGROUND: Asthma is a chronic respiratory disease characterized by reversible bronchoconstriction and airway inflammation. According to Statistics Canada in 2014, 8.1% of Canadians aged 12 and older reported having asthma diagnosed by a health care professional. Therefore, in 2014 there were an estimated 274,661 persons with asthma in Alberta. Most epidemiological studies estimate prevalence and incidence using survey-based data, which has limitations. The Ontario Asthma Surveillance Information System (OASIS) group has developed and validated an algorithm for epidemiologic asthma studies using provincial health databases. In Alberta, there are some studies using provincial databases, but most are restricted to emergency department visits and do not represent the entire asthma population. Using the validated asthma definition for epidemiologic studies, we performed an analysis of the Alberta Health administrative databases to investigate and report province-wide asthma prevalence, incidence and mortality in Alberta from 1995 to 2015. METHODS: Data from administrative databases, provided by Alberta Health, was analyzed to determine age and sex specific prevalence, incidence and mortality of the asthma population. The population cohort was all individuals residing in the province of Alberta, ages 0 to 99 from 1995-2015. Kendall's Tau coefficient test was used to ascertain whether the observed trends were statistically significant. RESULTS: Between 1995 and 2015, the age-standardized incidence of asthma decreased by more than 50% in both males and females. Prevalence, however, increased threefold over the 20 years (for both genders) from 3.9 to 12.3% (Tau = 1.00, p < 0.0001) in females and from 3.5 to 11.6% (Tau = 1.00, p < 0.0001) in males. Thus, in 2015 there were 496,927 people with asthma in Alberta. All-cause mortality in the asthma population decreased over time, in both females (Tau = - 0.71, p < 0.0001) and males (Tau = - 0.69, p = 0.0001). For the last several years, all-cause mortality was higher in those with asthma. There were ~ 7 deaths/1000 in the population with asthma versus ~ 5 deaths/1000 in those without asthma. CONCLUSIONS: The incidence of asthma decreased in both females and males while prevalence continued to increase, although at a slower rate than previously. All-cause mortality in asthma patients was higher than in those without asthma, but both decreased over time.

Stability of peripheral blood immune markers in patients with asthma.

BACKGROUND: Asthma is a complex disease with variable course. Efforts to identify biomarkers to predict asthma severity, the course of disease and response to treatment have not been very successful so far. We have previous suggested that PAR-2 and CRTh2 expression on specific peripheral blood cell subtypes may be biomarkers of asthma severity. We reasoned that parameters that remain stable when asthma symptoms are controlled would be the most appropriate to evaluate for their utility to predict loss of asthma control and/or severity of the disease. METHODS: Nineteen stable asthmatics were recruited from the University of Alberta Asthma clinic and followed in clinic every 3 months for a total of 4 visits. Patients had spirometry and completed the ACQ questionnaire in every visit. Blood was drawn in every visit and analyzed for a number of immune parameters by flow cytometry. These parameters included PAR-2 and CRTh2 expression on monocyte subgroups and T lymphocytes respectively, as well as numbers of eosinophils, innate lymphoid type-2 cells (ILC2) and dendritic cells. Within person stability of immune and physiological parameters was calculated using the intraclass correlation (ICC) using R version 3.4.0. RESULTS: FEV1 (% predicted), FEV1/FVC ratio, ACQ5 and ACQ7 did not differ significantly over the 4 visits, as would be expected for patients with stable asthma. Peripheral blood eosinophil numbers by Kimura stain and by flow cytometry showed ICC scores of 0.44 and 0.52 respectively, indicating moderate stability. The % of ILC2 cells in peripheral blood also showed moderate stability [ICC score of 0.45 (0.14-0.67)]. The stability for all other immune parameters was poor. CONCLUSION: Among the peripheral blood immune parameters we studied, only numbers of eosinophils and ILC2 in peripheral blood were moderately stable over a year in stable asthmatics. Further studies are required to understand the reasons for the variability of the other cell types.

Insights into the activity, differential expression, mutual regulation, and functions of matrix metalloproteinases and a disintegrin and metalloproteinases in hypertension and cardiac disease.

Hypertensive cardiac disease is a major cause of death worldwide. Causative factors of hypertension include environmental stressors, genetic predisposition, and common morbidities of lipid metabolism such as obesity and diabetes. These factors pathologically elevate the systemic production of vasoconstrictive G-protein-coupled receptor agonists. Pathological concentrations of these agonists upregulate the gene expression and proteolytic activity of matrix metalloproteinases (MMPs) and A disintegrin and metalloproteinases (ADAMs). Among the metalloproteinases that act in concert with other mediators to elevate the systemic blood pressure and to modulate the development of cardiovascular hypertrophy and fibrosis processes are MMP-2, MMP-7, ADAM-12, and ADAM-17. This review offers insights into the activity, differential expression, mutual regulation, and functions of these metalloproteinases. We further review evidence linking them to transcription factors, carrier proteins, and receptors for lipids. The emerging links between metalloproteinases and lipids are intriguing and suggest new therapeutic targets in hypertensive cardiac disease.

Molecular Signals Elicited by GPCR Agonists in Hypertension, Cardiovascular Remodeling: Are MMPs and ADAMs Elusive Therapeutic Targets?

Hypertension, the condition characterized by sustained elevated blood pressure, affects over 25% of adults in developed countries and is accompanied by pathological cardiac remodeling (i.e., hypertrophy and fibrosis), thus being a major risk factor for cardiac failure. Life style, the environment, genetic factors, diabetes or obesity can all promote development and progression of hypertension associated cardiovascular disease in part because these conditions induce an excess production of pro-hypertensive, pro-hypertrophic and pro-fibrotic agonists. Here we review signaling pathways shared by major agonists including angiotensin II, catecholamines and endothelins. At the cellular level, these agonists initiate disease signaling by activating cognate G protein-coupled receptors (GPCRs). Early events in agonist-signaling include Ca2+ release from intracellular stores, Ca2+ uptake from extracellular millieu into cells and reactive oxygen species (ROS) generation by NADPH oxidase. ROS production in turn contributes to activation of matrix metalloproteinases (MMPs) and 'a disintegrin and metalloproteinases' (ADAMs). Activated MMPs and ADAMs cleave growth factors, cytokines as well as cell surface receptors, including GPCRs. Excessive activation of MMPs and ADAMs links agonist receptors with transcription and translation of disease-associated genes, including those of MMPs and ADAMs. Recent research indicates a complex and dynamic regulation of MMPs and ADAMs activity and expression by agonists, which poses a significant challenge to strategies aiming at targeting specific MMPs or ADAMs in cardiovascular disease.

Metalloproteinases: key and common mediators of multiple GPCRs and candidate therapeutic targets in models of hypertensive cardiac disease.

Hypertensive cardiac disease remains a major cause of death worldwide because its typically complex etiology renders current treatments ineffective. Primary causative factors include environmental stressors, genetic predisposition and metabolic morbidities such as obesity and diabetes. These factors all trigger a systemic pathological production of agonists of G-protein-coupled receptors (GPCRs). When produced in excess, GPCR agonists transactivate many metalloproteinases, which relay agonist signaling. Here we review evidence supporting a global therapeutic concept for treatment of hypertensive cardiac disease with complex or unknown etiology by targeting common mediators of multiple GPCRs such as metalloproteinases and their downstream effectors.

Metalloproteinases in hypertension and cardiac disease: differential expression and mutual regulation.

Arterial hypertension, a condition characterized by sustained elevated blood pressure, is associated with pathological cardiac remodeling (i.e. cardiac hypertrophy and fibrosis) and is a major risk factor for cardiac failure. These processes can be triggered by excess vasoconstrictive agonists, which induce metalloproteinase-dependent shedding of growth factors to transactivate growth factor receptors and initiate disease signaling. Here, we review emerging evidence that agonist-activated metalloproteinases exhibit different expression patterns and mutual transcriptional regulation during the development of hypertension and cardiac remodeling.