Pathogenesis
Aparna Palit, Arun C. Inamadar in Systemic Sclerosis, 2019
Innate immune response recognizes the pathogen-associated molecular pattern (PAMP) via pattern recognition receptors (PRR) expressed widely on cells of immune system and FBs. TLRs, as part of circulating PRRs, play a significant role in the pathogenesis of SSc. Upon recognition of PAMPs, the TLRs stimulate the production and secretion of pro-inflammatory cytokines such as type 1 interferon (IFN), which is a regulator of innate immune system. It is produced mainly by plasmacytoid dendritic cells (DC). The dysregulation of type 1 IFN and IFN-inducible genes have been reported in patients with SSc. In the early stage of skin involvement, activated macrophages that are present around the blood vessels secrete CCL-2, TGF-β, PDGF, and INF-regulated Sialic acid-binding immunoglobulin-1 involved in the pathogenesis of SSc. The mast cells that are present around myofibroblasts in SSc also secrete inflammatory mediators like TGF-β, IL-4, IL-13, PDGF, monocytic chemotactic protein-1 (MCP-1), IFN-α, and ET-1. TGF-β secreted by mast cells, or macrophages, or the activation of TLR causes differentiation of FBs into myofibroblasts. These cells promote production of collagen leading to fibrosis. Thus, activation of innate immunity not only promotes pathogenesis, but also precedes adaptive immune response.3
Imaging of Thrombosis
Hau C. Kwaan, Meyer M. Samama in Clinical Thrombosis, 2019
Other secondary signs of venous thrombosis, such as the presence of collateral pathways and changes in size of involved organs, are demonstrable on ultrasound examinations just as on CT,241–247 and the specifics will not be detailed again. In addition, the echogenicity of involved organs may be affected by thrombosis. Early in the course of renal vein thrombosis, for example, decreased cortical echogenicity may occur,246,247 probably due to edema or hemorrhage. In chronic renal vein thrombosis concomitant with decrease in the renal size, the cortical echogenicity may increase and the normal sonographic differentiation between cortex and medulla may be lost.246 These findings are correlated with the development of fibrosis pathologically.
Pathology of Human Bladder Cancer and Related Lesions
George T. Bryan, Samuel M. Cohen in The Pathology of Bladder Cancer, 2017
Radiation cystitis occurs in patients undergoing irradiation for pelvic tumors other than those in the bladder or for bladder carcinoma. Symptoms may appear as early as 4 to 6 weeks after initiation of therapy, but may be delayed for months or even years.94 There is injury to the microcirculation below the basal layer of the epithelium. The mucosa becomes red and edematous and focal desquamation occurs. Later on, fibrosis of the bladder wall, atrophy of the epithelium, and telangiectasia develop. Painless, but often severe, hematuria may originate from these dilated vessels. Obliteration of the lumen of larger arteries causes ischemia with necrosis and ulceration of the mucosa. Bizarre fibroblasts are noted in the subepithelial connective tissue which is often edematous. In later stages, there may be marked fibrosis. The administration of cyclophosphamide appears to act synergistically with irradiation.
A patent review of discoidin domain receptor 1 (DDR1) modulators (2014-present)
Published in Expert Opinion on Therapeutic Patents, 2020
Fibrosis is a consequence of the synthesis and accumulation of extracellular matrix in the corresponding tissues. DDR1 binds all types of collagens and is widely expressed in a variety of tissues, including vascular smooth muscle, mesangial, and renal epithelial cells and macrophages [34,35]. DDR1 null mice have been reported to protect against renal vascular lesions induced by a long-term infusion of angiotensin II, a model in which hemodynamic alterations and vascular remodeling play a major role. It was observed that angiotensin II treated mice developed serious perivascular, interstitial inflammation, and fibrosis. Whereas, DDR1-deficient mice displayed reduced accumulation of fibrillar collagen and transforming growth factor expression. This study underlined a major role of DDR1 in kidney disease progression [36]. Another study also investigated the role of DDR1 in cell–matrix interaction involved in the pathogenesis of Alport syndrome including renal inflammation and fibrosis. It was shown that loss of DDR1-expression in kidney delayed renal fibrosis and inflammation in hereditary type IV collagen disease [37].
Nintedanib for the treatment of systemic sclerosis-associated interstitial lung disease
Published in Expert Review of Clinical Immunology, 2020
Yoshioki Yamasaki, Masataka Kuwana
Early inflammation resulted in the activation of the profibrotic phenotype of fibroblasts, which possess a gene and protein expression profile of transforming growth factor-beta (TGF-β) activation. The intracellular pathways that are activated by TGF-beta signaling include the canonical Smad2/3 pathway and non-canonical pathways, such as mitogen-activated protein kinases, c-abl, JAK2/STAT3, and Rho-associated kinases, which controls MITF-A and YAP [6,10,11]. Growth factors, including platelet-derived growth factor (PDGF), fibroblast growth factor (FGF) and, vascular endothelial growth factor (VEGF), are released from the damaged epithelium and endothelium [12]. Moreover, fibroblasts are drawn from different sites of injury, proliferate, migrate, and acquire features of smooth muscle cells and become myofibroblasts [12,13]. In addition, fibrocytes from the circulation invade, and epithelial cells [14], endothelial cells, and pericytes [15] acquire features usually associated with myofibroblasts through a process called epithelial- or endothelial-mesenchymal transition. These pathways collaboratively lead to the dysregulated accumulation of collagen and extracellular matrix components, and ultimately excessive fibrosis. The severity of this process could be influenced by the activity of the disease.
Origins of fibroblasts in rheumatoid synovial tissues: Implications from organ fibrotic models
Published in Modern Rheumatology, 2018
Yusuke Matsuo, Tetsuya Saito, Akio Yamamoto, Hitoshi Kohsaka
Organ fibrosis is also a disease of which fibroblasts play crucial roles in the pathogenesis. In contrast to RA, organ fibrosis is characterized by excessive deposition of extracellular matrix proteins, but not inflammation. However, increased numbers of fibroblasts in tissues are common histological findings in both organ fibrosis and RA. In this regard, several studies have already revealed the cellular origins of fibroblasts in fibrotic tissues in murine models of organ fibrosis. In particular, lineage tracing, which is one of the methods leading to convincing results, was performed using transgenic mice in some studies. Thus, we assume that the cellular origins of fibroblasts in organ fibrotic tissues may imply those of fibroblasts in rheumatoid synovial tissues. This review is to summarize and discuss available evidence for the origins of fibroblasts in arthritic synovial tissues and organ fibrotic tissues.