Pulmonary 5-HT receptor expression in fibrotic interstitial lung diseases.

Pulmonary fibrosis is a severe condition in interstitial lung diseases (ILD) such as idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-ILD, where the underlying mechanism is not well defined and with no curative treatments available. Serotonin (5-HT) signaling via the 5-HT receptor has been recognized as a promising preclinical target for fibrosis. Despite this, the involvement of the 5-HT receptor in fibrotic ILD is widely unexplored.

Targeting serotonin receptor 2B inhibits TGFβ induced differentiation of human vascular smooth muscle cells.

Vascular Smooth Muscle Cells (VSMCs) are known to be the key drivers of intimal thickening which contribute to early progression of atherosclerosis. VSMCs are the major producers of extracellular matrix within the vessel wall and in response to atherogenic stimuli they could modify the type of matrix proteins produced. Serotonin receptor 2B (5-HT receptor/HTR2B) has been implicated in several chronic fibrotic and vascular diseases.

Pathological Insight into 5-HT Receptor Activation in Fibrosing Interstitial Lung Diseases.

Interstitial lung disease (ILD) encompasses a heterogeneous group of more than 200 conditions, of which primarily idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia, hypersensitivity pneumonitis, ILD associated with autoimmune diseases and sarcoidosis may present a progressive fibrosing (PF) phenotype. Despite different aetiology and histopathological patterns, the PF-ILDs have similarities regarding disease mechanisms with self-sustaining fibrosis, which suggests that the diseases may share common pathogenetic pathways. Previous studies show an enhanced activation of serotonergic signaling in pulmonary fibrosis, and the serotonin (5-HT) receptors have been implicated to have important roles in observed profibrotic actions.

Effects of 5-Hydroxytryptamine Class 2 Receptor Antagonists on Bronchoconstriction and Pulmonary Remodeling Processes.

Serotonin [5-hydroxytryptamine (5-HT)] is associated with several chronic pulmonary diseases, recognizing 5-HT receptor antagonists as potential inhibitors of tissue remodeling. However, the effects of 5-HT receptors, especially 5-HT receptors on airway function and remodeling, are unclear. We investigated the role of 5-HT receptors on airway smooth muscle contractility and remodeling processes.

Pulmonary fibrosis in vivo displays increased p21 expression reduced by 5-HT receptor antagonists in vitro - a potential pathway affecting proliferation.

Serotonin (5-hydroxytryptamine) has repeatedly been associated with the development of fibrotic disorders such as pulmonary fibrosis. By blocking the binding of 5-HT to 5-HT receptors with receptor antagonists, several pro-fibrotic mechanisms can be inhibited. Bleomycin-induced pulmonary fibrosis is a model used to evaluate pathological mechanisms and pharmacological interventions.

5-HT2B receptor antagonists attenuate myofibroblast differentiation and subsequent fibrotic responses in vitro and in vivo.

Pulmonary fibrosis is characterized by excessive accumulation of connective tissue, along with activated extracellular matrix (ECM)-producing cells, myofibroblasts. The pathological mechanisms are not well known, however serotonin (5-HT) and 5-HT class 2 (5-HT2) receptors have been associated with fibrosis. The aim of the present study was to investigate the role of 5-HT2B receptors in fibrosis, using small molecular 5-HT2B receptor antagonists EXT5 and EXT9, with slightly different receptor affinity.

Type I interferon-mediated skewing of the serotonin synthesis is associated with severe disease in systemic lupus erythematosus.

Serotonin, a highly pro-inflammatory molecule released by activated platelets, is formed by tryptophan. Tryptophan is also needed in the production of kynurenine, a process mediated by the type I interferon (IFN)-regulated rate-limiting enzyme indoleamine 2,3-dioxygenase (IDO). The aim of this study was to investigate levels of serotonin in patients with the autoimmune disease systemic lupus erythematosus (SLE), association to clinical phenotype and possible involvement of IDO in regulation of serotonin synthesis.

The skeletal phenotype of chondroadherin deficient mice.

Chondroadherin, a leucine rich repeat extracellular matrix protein with functions in cell to matrix interactions, binds cells via their α2β1 integrin as well as via cell surface proteoglycans, providing for different sets of signals to the cell. Additionally, the protein acts as an anchor to the matrix by binding tightly to collagens type I and II as well as type VI. We generated mice with inactivated chondroadherin gene to provide integrated studies of the role of the protein.

Identification and characterization of the integrin alpha2beta1 binding motif in chondroadherin mediating cell attachment.

Chondroadherin is a leucine-rich repeat protein known to mediate adhesion of isolated cells via the integrin α(2)β(1) and to interact with collagen. In this work, we show that cell adhesion to chondroadherin leads to activation of MAPKs but does not result in cell spreading and division. This is in contrast to the spreading and dividing of cells grown on collagen, although the binding is mediated via the same α(2)β(1) receptor.

Purification, crystallization and preliminary X-ray diffraction analysis of human chondroadherin.

Chondroadherin is a cartilage matrix protein that is known to mediate the adhesion of isolated chondrocytes. Its protein core is composed of 11 leucine-rich repeats flanked by cysteine-rich domains at the N- and C-terminal ends. Recombinant human chondroadherin was crystallized using the sitting-drop vapour-diffusion method.

Differential adherence of osteoarthritis and rheumatoid arthritis synovial fibroblasts to cartilage and bone matrix proteins and its implication for osteoarthritis pathogenesis.

In osteoarthritis (OA), cartilage and bone fragments have been described within the synovial tissue which are surrounded by synovial cells (i.e. detritus synovitis).

Biglycan organizes collagen VI into hexagonal-like networks resembling tissue structures.

The ability of the leucine-rich repeat (LRR) proteins biglycan, decorin, and chondroadherin to interact with collagen VI and influence its assembly to supramolecular structures was studied by electron microscopy and surface plasmon resonance measurements in the BIAcore 2000 system. Biglycan showed a unique ability to organize collagen VI into extensive hexagonal-like networks over a time period of only a few minutes. Only the intact molecule, substituted with two dermatan sulfate chains, had this capacity.

Association of chondroadherin with collagen type II.

Chondroadherin is a cell binding, leucine-rich repeat protein found in the territorial matrix of articular cartilage. Several members of the leucine-rich repeat protein family present in the extracellular matrix of e.g.