Cellular Fibronectin is Induced in Ultraviolet-Exposed Human Skin and Induces IL-10 Production by Monocytes/Macrophages

CD11b+ monocytic/macrophagic cells that infiltrate human skin after in vivo ultraviolet exposure potently produce interleukin-10. We hypothesized that binding of monocyte β1 integrins to ultraviolet-induced extracellular matrix ligands, such as fibronectin, after entry of blood monocytes into the dermis, is involved in the modulation of immunoregulatory monocytic cytokines. Immunostaining of human skin and reverse transcriptase–polymerase chain reaction studies revealed that the embryonic isoform of cellular fibronectin, in which the extra domain A (EDA) segment is spliced in (EDA+ cellular fibronectin), and confers enhanced binding to β1 integrins, is newly induced and is associated with infiltrating CD11b+ cells post in vivo ultraviolet exposure. We then tested the effect of fibronectin on resting purified peripheral monocytes in vitro. We found that monocyte interleukin-10, but not interleukin-12, was significantly induced in a concentration-dependent manner by in vitro binding to cellular fibronectin (n = 6), but not plasma fibronectin. Tumor necrosis factor-α was also induced in a concentration-dependent manner, but to a lesser extent. Monoclonal antibodies to β1 integrins β-subunit (CD29) also strongly induced tumor necrosis factor-α and interleukin-10 production, but not interleukin-12. Neutralization of tumor necrosis factor-α reduced by 54% the interleukin-10 production that was induced by monocytes binding to cellular fibronectin, indicating that interleukin-10 induction is at least in part dependent upon concomitant autocrine tumor necrosis factor-α release. In conclusion, ultraviolet skin injury results in increased production and deposition of EDA+ cellular fibronectin in the papillary dermis, which may be one of the key signals capable of inducing interleukin-10 but not interleukin-12 in monocytes that infiltrate micromilieu of human skin after ultraviolet exposure

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570