Fibrosis is a debilitating condition that can lead to impairment of the affected organ's function. Excessive deposition of extracellular matrix (ECM) molecules is characteristic of most fibrotic tissues. Fibroblasts activated by cytokines or growth factors differentiate into myofibroblasts that drive fibrosis by depositing ECM molecules, such as collagen, fibronectin, and connective tissue growth factor. Transforming growth factor-β (TGF-β) is one of the major profibrotic cytokines which promotes fibrosis by signaling abnormal ECM regulation. Hyaluronan (HA) is a major ECM glycosaminoglycan that is regulated by TGF-β and whose role in fibrosis is emerging. Aside from its role as a hydrating, space filling polymer, HA regulates different cellular functions and is known to have a role in wound healing and inflammation. Importantly, HA deposition is increased in multiple fibrotic diseases. In this review we highlight studies that link HA to fibrosis and discuss what is known about the role of HA, its receptors, and its anabolic and catabolic enzymes in different fibrotic diseases.

Background & Aims Crohn’s Disease (CD) is a chronic inflammatory disease of the gastrointestinal tract. Fibrosis, a serious complication of CD, occurs when activated intestinal fibroblasts deposit excessive amounts of extracellular matrix (ECM) in affected areas. A major component of the ECM is high molecular weight hyaluronan (HA) which, when depolymerized to low molecular weight fragments, becomes pro-inflammatory and pro-fibrotic. Mechanisms for HA degradation are incompletely understood, but the novel protein KIAA1199 was recently discovered to degrade HA. We hypothesize that KIAA1199 protein is increased in CD colon fibroblasts and generates HA fragments that foster inflammation and fibrosis. Methods Fibroblasts were isolated from explants of surgically resected colon tissue from CD and non-IBD control (ND) patients. Protein levels and tissue distribution of KIAA1199 were assessed by immunoblot and immunostaining, and functional HA degradation was measured biochemically. Results Elevated levels of KIAA1199 protein were produced and deposited in the ECM by cultured CD fibroblasts compared to controls. Treatment of fibroblasts with the pro- inflammatory cytokine interleukin-6 (IL-6) increased deposition of KIAA1199 in the ECM. CD fibroblasts also produce significantly higher levels of IL-6 compared to controls, and antibody blockade of IL-6 receptors in CD colon fibroblasts decreased the level of KIAA1199 protein in the ECM. Colon fibroblasts degrade HA, however siRNA silencing of KIAA1199 abrogated that ability. Conclusions CD fibroblasts produce elevated levels of KIAA1199 primarily through an IL-6 driven autocrine mechanism. This leads to excessive degradation of HA and the generation of pro-inflammatory HA fragments that contributes to maintenance of gut inflammation and fibrosis.

• Platelet HYAL2 is stored in a-granules and upon activation it becomes surface expressed where it functions to degrade extracellular matrix.• Platelets from IBD patients contain lower HYAL2 protein and activity than those from non-IBD controls.Following injury, platelets rapidly interact with the exposed extracellular matrix (ECM) of the vessel wall and the surrounding tissues. Hyaluronan (HA) is a major glycosaminoglycan component of the ECM and plays a significant role in regulating inflammation. We have recently reported that human platelets degrade HA from the surfaces of activated endothelial cells into fragments capable of inducing immune responses by monocytes. We also showed that human platelets contain the enzyme hyaluronidase-2 (HYAL2), one of two major hyaluronidases that digest HA in somatic tissues. The deposition of HA increases in inflamed tissues in several inflammatory diseases, including inflammatory bowel disease (IBD). We therefore wanted to define the mechanism by which platelets degrade HA in the inflamed tissues. In this study, we show that human platelets degrade the proinflammatory matrix HA through the activity of HYAL2 and that platelet activation causes the immediate translocation of HYAL2 from a distinct population of a-granules to platelet surfaces where it exerts its catalytic activity. Finally, we show that patients with IBD have lower platelet HYAL2 levels and activity than healthy controls. (Blood. 2015; 125(9):1460-1469 Introduction Hyaluronan (HA) is a ubiquitous glycosaminoglycan and a major component of the extracellular matrix (ECM), and it has a crucial role in regulating inflammation.1 HA is produced by the HA synthase enzymes (HAS1-3) and is composed of repeating disaccharides of D-glucuronic acid and N-acetylglucosamine. Not only can HA be synthesized and released, but it can also form a voluminous pericellular coat that surrounds cells. The HA coat is either anchored to the cell surface through binding to specific cell-surface receptors, such as CD44, or it can be retained at the cell surface by sustained transmembrane interactions with its synthases.2 Interestingly, a growing body of literature suggests that different sizes of HA exert a wide spectrum of functions.3 Under normal conditions in tissues, HA is present in its high molecular weight (HMWHA) form (1 to 10 3 10 6 Da). HMWHA functions as a structural hydrating polymer and is also known to be antiinflammatory, 4 protecting from T-cellmediated liver injury and bleomycin-mediated lung injury in mice. 5,6 HMWHA also promotes the suppressive effects of regulatory CD4 1 CD251 T cells. 7Increased HA deposition has also been reported in many inflammatory diseases including inflammatory bowel disease (IBD), arthritis, and asthma. [8][9][10] Importantly, degradation of HA results in HA fragments that function as damage-associated molecular patterns. 11Fragmented HA contributes to wound healing, angiogenesis, and inflammation and is capable of signaling cellular responses through specific receptors. 12 For example, HA ...

Objective: COVID-19 and associated morbidity and mortality has disproportionately affected minoritized populations. The epidemiology of spread of COVID-19 among pregnant women by race/ethnicity is not well described. Using data from a large healthcare system in California, we estimated prevalence and spread during pregnancy and recommend a vaccination approach based on minimizing adverse outcomes. Methods: Patients delivering at Sutter Health are tested (molecular) for COVID-19. These results were combined with antibody test results, using samples drawn at delivery. For each racial/ethnic group, we estimated prevalence of COVID-19, using logistic regression to adjust for known sociodemographic and comorbid risk factors. Testing for immunoglobulin G and immunoglobulin M provided insight into timing of infections. Results: Among 17,446 women delivering May–December, 460 (2.6%) tested positive (molecular). Hispanic women were at 2.6 times the odds of being actively infected as White women (odds ratio = 2.6, 95% confidence interval = 2.0–3.3). August and December were the highest risk periods for active infection (odds ratio = 3.5, 95% confidence interval = 2.1–5.7 and odds ratio = 6.1, 95% confidence interval = 3.8–9.9, compared with May, respectively). Among 4500 women delivering October–December, 425 (9.4%) had positive molecular or antibody tests, ranging from 4.0% (Asian) to 15.7% (Hispanic). Adjusting for covariables, compared with White patients, odds of infection was similar for Black and Asian patients, with Hispanic at 2.4 (1.8–3.3) times the odds. Conclusion: COVID-19 prevalence was higher among Hispanic women at delivery and in the last trimester than their White counterparts. Higher rates in Black patients are explained by other risk factors. Resources should be directed to increase vaccination rates among Hispanic women in early stages of pregnancy.