Osteoprotegerin is an Early Marker of the Fibrotic Process and of Antifibrotic Treatment Responses in Ex Vivo Lung Fibrosis.

Background: Lung fibrosis is a chronic lung disease with a high mortality rate with only two approved drugs (pirfenidone and nintedanib) to attenuate its progression. To date, there are no reliable biomarkers to assess fibrosis development and/or treatment effects for these two drugs. Osteoprotegerin (OPG) is used as a serum marker to diagnose liver fibrosis and we have previously shown it associates with lung fibrosis as well.

Osteoprotegerin is More than a Possible Serum Marker in Liver Fibrosis: A Study into its Function in Human and Murine Liver.

Osteoprotegerin (OPG) serum levels are associated with liver fibrogenesis and have been proposed as a biomarker for diagnosis. However, the source and role of OPG in liver fibrosis are unknown, as is the question of whether OPG expression responds to treatment. Therefore, we aimed to elucidate the fibrotic regulation of OPG production and its possible function in human and mouse livers.

Enhanced Bruton's tyrosine kinase in B-cells and autoreactive IgA in patients with idiopathic pulmonary fibrosis.

Rationale: Idiopathic Pulmonary Fibrosis (IPF) is thought to be triggered by repeated alveolar epithelial cell injury. Current evidence suggests that aberrant immune activation may contribute. However, the role of B-cell activation remains unclear.

Dual role of YM1+ M2 macrophages in allergic lung inflammation.

Alternatively activated (M2 or YM1+) macrophages have been associated with the development of asthma but their contribution to disease initiation and progression remains unclear. To assess the therapeutic potential of modulating these M2 macrophages, we have studied inhibition of M2 polarisation during and after development of allergic lung inflammation by treating with cynaropicrin, a galectin-3 pathway inhibitor. Mice that were treated with this inhibitor of M2 polarisation during induction of allergic inflammation developed less severe eosinophilic lung inflammation and less collagen deposition around airways, while the airway α-smooth muscle actin layer was unaffected.

A Potent Tartrate Resistant Acid Phosphatase Inhibitor to Study the Function of TRAP in Alveolar Macrophages.

The enzyme tartrate resistant acid phosphatase (TRAP, two isoforms 5a and 5b) is highly expressed in alveolar macrophages, but its function there is unclear and potent selective inhibitors of TRAP are required to assess functional aspects of the protein. We found higher TRAP activity/expression in lungs of patients with chronic obstructive pulmonary disease (COPD) and asthma compared to controls and more TRAP activity in lungs of mice with experimental COPD or asthma. Stimuli related to asthma and/or COPD were tested for their capacity to induce TRAP.

PGE2-treated macrophages inhibit development of allergic lung inflammation in mice.

In healthy lungs, many macrophages are characterized by IL-10 production, and few are characterized by expression of IFN regulatory factor 5 (formerly M1) or YM1 and/or CD206 (formerly M2), whereas in asthma, this balance shifts toward few producing IL-10 and many expressing IFN regulatory factor 5 or YM1/CD206. In this study, we tested whether redressing the balance by reinstating IL-10 production could prevent house dust mite-induced allergic lung inflammation. PGE2 was found to be the best inducer of IL-10 in macrophages in vitro.

Sexual maturation protects against development of lung inflammation through estrogen.

Increasing levels of estrogen and progesterone are suggested to play a role in the gender switch in asthma prevalence during puberty. We investigated whether the process of sexual maturation in mice affects the development of lung inflammation in adulthood and the contributing roles of estrogen and progesterone during this process. By inducing ovalbumin-induced lung inflammation in sexually mature and immature (ovariectomized before sexual maturation) adult mice, we showed that sexually immature adult mice developed more eosinophilic lung inflammation.

Macrophage heterogeneity in respiratory diseases.

Macrophages are among the most abundant cells in the respiratory tract, and they can have strikingly different phenotypes within this environment. Our knowledge of the different phenotypes and their functions in the lung is sketchy at best, but they appear to be linked to the protection of gas exchange against microbial threats and excessive tissue responses. Phenotypical changes of macrophages within the lung are found in many respiratory diseases including asthma, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis.

Characterization of macrophage phenotypes in three murine models of house-dust-mite-induced asthma.

In asthma, an important role for innate immunity is increasingly being recognized. Key innate immune cells in the lungs are macrophages. Depending on the signals they receive, macrophages can at least have an M1, M2, or M2-like phenotype.