In AKI, dying renal cells release intracellular molecules that stimulate immune cells to secrete proinflammatory cytokines, which trigger leukocyte recruitment and renal inflammation. Whether the release of histones, specifically, from dying cells contributes to the inflammation of AKI is unknown. In this study, we found that dying tubular epithelial cells released histones into the extracellular space, which directly interacted with Toll-like receptor (TLR)-2 (TLR2) and TLR4 to induce MyD88, NF-kB, and mitogen activated protein kinase signaling. Extracellular histones also had directly toxic effects on renal endothelial cells and tubular epithelial cells in vitro. In addition, direct injection of histones into the renal arteries of mice demonstrated that histones induce leukocyte recruitment, microvascular vascular leakage, renal inflammation, and structural features of AKI in a TLR2/TLR4-dependent manner. Antihistone IgG, which neutralizes the immunostimulatory effects of histones, suppressed intrarenal inflammation, neutrophil infiltration, and tubular cell necrosis and improved excretory renal function. In summary, the release of histones from dying cells aggravates AKI via both its direct toxicity to renal cells and its proinflammatory effects. Because the induction of proinflammatory cytokines in dendritic cells requires TLR2 and TLR4, these results support the concept that renal damage triggers an innate immune response, which contributes to the pathogenesis of AKI.

AKI involves early Toll-like receptor (TLR)-driven immunopathology, and resolution of inflammation is needed for rapid regeneration of injured tubule cells. Notably, activation of TLRs also has been implicated in epithelial repair. We hypothesized that TLR signaling drives tubule regeneration after acute injury through the induction of certain ILs. Systematic screening in vitro identified IL-22 as a candidate proregeneratory factor in primary tubular cell recovery, and IL-22 deficiency or IL-22 blockade impaired postischemic tubular recovery after AKI in mice. Interstitial mononuclear cells, such as dendritic cells and macrophages, were the predominant source of IL-22 secretion, whereas IL-22 receptor was expressed by tubular epithelial cells exclusively. Depleting IL-22-producing cells during the healing phase impaired epithelial recovery, which could be rescued entirely by reconstituting mice with IL-22. In vitro, necrotic tubular cells and oxidative stress induced IL-22 secretion selectively through TLR4. Although TLR4 blockade during the early injury phase prevented tubular necrosis and AKI, TLR4 blockade during the healing phase suppressed IL-22 production and impaired kidney regeneration. Taken together, these results suggest that necrotic cell-derived TLR4 agonists activate intrarenal mononuclear cells to secrete IL-22, which accelerates tubular regeneration and recovery in AKI.

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Background Chronic rhinosinusitis is regarded as a chronic airway disease. According to WHO recommendations, it may be a risk factor for COVID‐19 patients. In most CRSwNP cases, the inflammatory changes affecting the nasal and paranasal mucous membranes are type‐2 (T2) inflammation endotypes. Methods The current knowledge on COVID‐19 and on treatment options for CRS was analyzed by a literature search in Medline, Pubmed, international guidelines, the Cochrane Library and the Internet. Results Based on international literature, on current recommendations by WHO and other international organizations as well as on previous experience, a panel of experts from EAACI and ARIA provided recommendations for the treatment of CRS during the COVID‐19 pandemic. Conclusion Intranasal corticosteroids remain the standard treatment for CRS in patients with SARS‐CoV‐2 infection. Surgical treatments should be reduced to a minimum and surgery preserved for patients with local complications and for those with no other treatment options. Systemic corticosteroids should be avoided. Treatment with biologics can be continued with careful monitoring in noninfected patients and should be temporarily interrupted during the course of the COVID‐19 infection.

Objective Endoscopic resection of sinonasal cancer has become an alternative to open craniofacial surgery and leads to safe and satisfying results in emerging numbers. Randomized study data comparing outcomes between approaches are missing. Hence, it remains unclear which subgroups of patients might profit most from each technique. We aimed to identify such patient and tumor characteristics and gather information for future prospective study design. Study Design Case series with chart review. Setting Tertiary academic center. Subjects and Methods This study is based on a retrospective chart review of 225 patients undergoing open craniofacial or endoscopic resection for sinonasal malignancy between 1993 and 2015 at Munich University Hospital. Statistical analyses include t test, chi-square, Kaplan-Meier charts, and univariate and multivariate analyses. Results The sample size was similar between the endoscopic and open surgery groups. Tumors were significantly larger in patients who underwent open craniofacial resection. The risk of notable bleeding (P = .041) was lower and hospital stay shorter (P = .001) for endoscopic interventions of all tumor stages. Rates of overall (P = .024) and disease-specific (P = .036) survival were significantly improved for endoscopic cases; improved recurrence-free survival rates did not achieve statistical significance (P = .357). For cases matched for tumor size, this improvement was confirmed for T3 tumors (P = .038). Regional and distant metastatic tumor spread generally worsened survival in both surgical subgroups. Multivariate Cox regression analysis revealed independent prognosticators for overall survival. Conclusion Endoscopic tumor resection remains a suitable option for distinct indications and showed improved outcome in intermediate-stage tumors in our collective. Further randomized studies acknowledging the here-identified factors are needed to improve future therapy guidelines and patient care.