Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that form a family of 24 members in mammals. Evidence of the pathological roles of MMPs in various diseases, combined with their druggability, has made them attractive therapeutic targets. Initial drug discovery efforts focused on the roles of MMPs in cancer progression, and more than 50 MMP inhibitors have been investigated in clinical trials in various cancers. However, all of these trials failed. Reasons for failure include the lack of inhibitor specificity and insufficient knowledge about the complexity of the disease biology. MMPs are also known to be involved in several inflammatory processes, and there are new therapeutic opportunities for MMP inhibitors to treat such diseases. In this Review, we discuss the recent advances made in understanding the role of MMPs in inflammatory diseases and the therapeutic potential of MMP inhibition in those conditions.

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Is there new hope for therapeutic matrix metalloproteinase inhibition

Matrix metalloproteinases in inflammation.

The receptor NLRP3 is central to the formation of inflammasomes in myeloid cells. Ghiringhelli and colleagues demonstrate that NLRP3 also serves an important inflammasome-independent role in CD4+ T cells, in which it helps coordinate TH2 differentiation.

The receptor NLRP3 is a transcriptional regulator of TH2 differentiation.

Commentary: IL-4 and IL-13 receptors and signaling

https://www.gastrojournal.org/article/S0016-5085(10)01320-X/pdf

The Spectrum of Achalasia: Lessons From Studies of Pathophysiology and High-Resolution Manometry

Inflammatory mediators are of considerable interest as potential therapeutic targets in various cancers. Here we investigate whether interleukin (IL)-4 receptor alpha (IL4Ralpha), a component of the receptor complex for the T helper 2 cytokines IL4 and IL13, plays a role in colonic tumorigenesis. IL4Ralpha protein expression was seen in tumor cells of 28/48 human colon adenocarcinomas on a tissue microarray. In human and murine colon tumor cell lines analyzed in vitro, all of which expressed IL4Ralpha, treatment with exogenous ligand resulted in dose-dependent increases in proliferation. IL4 decreased apoptosis only in HCT116 cells. An orthotopic allograft model was used to determine in vivo effects of tumor cell-specific IL4Ra ablation. MC38 murine tumor cells with the IL4Ra gene knocked down showed reduced proliferation but no difference in apoptosis compared with controls after implantation in ceca of syngeneic mice. Mice null for IL4Ra and wild-type controls were treated with azoxymethane and dextran sulfate sodium to induce tumor formation. Mice with global deletion of IL4Ra had significantly fewer and smaller tumors. Reduced tumorigenicity correlated with decreased proliferation and increased apoptosis. Systemic blockade of IL4Ralpha-IL4 interactions with a chimeric soluble receptor protein gave similar results in the cecal implant model. Thus, IL4Ralpha, a component of the IL4R and IL13R, contributes to tumor formation in a mouse model of colitis-associated cancer. Proliferation appears to be directly mediated via IL4Ralpha on the epithelial tumor cells. Survival may be an indirect response mediated via other host cells. Our results support therapeutic targeting of IL4Ralpha in colon cancer.

/pdf/epithelial-interleukin-4-receptor-expression-promotes-colon-36r3y4dq81.pdf

Epithelial interleukin-4 receptor expression promotes colon tumor growth

Lack of MMP10 exacerbates experimental colitis and promotes development of inflammation-associated colonic dysplasia

Organ transplant is the preferred treatment for end-stage organ disease, yet the majority of patients with end-stage organ disease are never placed on the transplant waiting list. Limited access to the transplant waiting list combined with the scarcity of the organ pool result in over 100,000 deaths annually in the United States. Patients face unique barriers to referral and acceptance for organ transplant based on social determinants of health, and patients from disenfranchised groups suffer from disproportionately lower rates of transplantation. Our objective was to review the literature describing disparities in access to organ transplantation based on social determinants of health to integrate the existing knowledge and guide future research.We conducted a scoping review of the literature reporting disparities in access to heart, lung, liver, pancreas and kidney transplantation based on social determinants of health (race, income, education, geography, insurance status, health literacy and engagement). Included studies were categorized based on steps along the transplant care continuum: referral for transplant, transplant evaluation and selection, living donor identification/evaluation, and waitlist outcomes.Our search generated 16,643 studies, of which 227 were included in our final review. Of these, 34 focused on disparities in referral for transplantation among patients with chronic organ disease, 82 on transplant selection processes, 50 on living donors, and 61 on waitlist management. In total, 15 studies involved the thoracic organs (heart, lung), 209 involved the abdominal organs (kidney, liver, pancreas), and three involved multiple organs. Racial and ethnic minorities, women, and patients in lower socioeconomic status groups were less likely to be referred, evaluated, and added to the waiting list for organ transplant. The quality of the data describing these disparities across the transplant literature was variable and overwhelmingly focused on kidney transplant.This review contextualizes the quality of the data, identifies seminal work by organ, and reports gaps in the literature where future research on disparities in organ transplantation should focus. Future work should investigate the association of social determinants of health with access to the organ transplant waiting list, with a focus on prospective analyses that assess interventions to improve health equity. 

/pdf/a-scoping-review-of-inequities-in-access-to-organ-transplant-3s053b2a.pdf

A scoping review of inequities in access to organ transplant in the United States

Given its mortality benefit, renal transplantation remains the ideal treatment modality for end stage renal disease in children. Despite the recent expansion of use in young children, the novel SARS-CoV-2 vaccine has not been universally accepted. Similarly, vaccine related state regulations are heterogenous. We present a cross-sectional analysis of institutional specific vaccination policies at US pediatric renal transplant centers and relationships to state legislation. We found that 36.1% of institutions require COVID-19 vaccination prior to transplant, while 17 states have current legislation prohibiting proof of vaccination as a means of access to public services. Of the 63.9% of transplant centers without immunization requirement, almost two-thirds are located in states without prohibitory regulations. Despite an unclear primary influence of institutional policy, our study demonstrates a lack of standardization and potential to create unnecessary inequities.

Felicitas L. Koller

Papers

Epithelial interleukin-4 receptor expression promotes colon tumor growth

Lack of MMP10 exacerbates experimental colitis and promotes development of inflammation-associated colonic dysplasia

A scoping review of inequities in access to organ transplant in the United States

A Current View of SARS-CoV-2 Vaccine Policies Amongst Pediatric Renal Transplant Centers and Relationships to State Policy.