Soluble factors of mesenchimal stem cells (FS-MSC) as a potential tool to reduce inflammation in donor’s lungs after hypovolemic shock

Objective: The shortage of viable lungs is still a major obstacle for transplantation. Trauma victims who represent potential lung donors commonly present hypovolemic shock leading to pulmonary inflammation and deterioration and rejection after transplantation. Seeking to improve lung graft, new approaches to donor treatment have been tested. This study focuses on treatment with mesenchymal stem cells (MSCs) or soluble factors produced by MSCs (FS-MSC) using a rat model for lung donors after hemorrhagic shock. Methods: Forty-eight rats were divided into four groups: Sham (n=12), animals without induction of hypovolemic shock; Shock (n=12), animals submitted to hypovolemic shock (mean arterial pressure 40 mmHg); MSC (n=12), animals submitted to hypovolemic shock and treated with MSCs, and FS (n=12), animals submitted to hypovolemic shock and treated with FS-MSC. The animals were subjected to a 50-minute hypovolemic shock (40 mmHg) procedure. The treated animals were monitored for 115 minutes. We performed histopathology of lung tissue and quantification of inflammatory markers (TNF-a, IL-1ß, IL-6, IL-10, iCAM and vCAM) in lung tissue and peripheral blood leukocytes (PBLs). Results: Hemorrhagic shock resulted in higher PBLs and neutrophil infiltrate in the lungs. FS animals had lower neutrophil density comparing with Shock and MSC animals (p<0.001). No differences in the cytokine levels in lung tissue were observed between the groups. Conclusions: The lungs of rats submitted to hemorrhagic shock and treated with FS-MSC showed reduced inflammation indicated in a decrease in lung neutrophil infiltrate.

Psoriasiform Dermatitis Developing during Treatment of Juvenile Idiopathic Arthritis with Tocilizumab

We present a case of psoriasiform dermatitis developing during the treatment of juvenile idiopathic arthritis with tocilizumab (TCZ). The keratotic erythema with central healing showed a periodicity of growing worse 1 week after TCZ infusion, and then disappeared within 3 weeks. Skin biopsy showed parakeratosis, microabscess, rete ridge elongation, and abundant lymphocytes as well as a few neutrophil infiltrate in the upper dermis. TCZ is a humanized monoclonal antibody against interleukin 6 (IL-6) receptor. IL-6 plays a critical role in the differentiation from naïve T cells into Th17 cells in cooperation with transforming growth factor-β. IL-6 may be important in psoriasis pathogenesis, and therefore this phenomenon may be the adverse effect. The mechanism of TCZ-associated psoriasiform dermatitis is unclear. The serum IL-6 level seems to be elevated transitorily after TCZ administration, probably due to the competitive inhibition of IL-6 receptor alpha to IL-6. Excess free IL-6 may effect on other IL-6 family receptors. Since TCZ does not alter serum IL-17F level, another cytokine may be involved in the psoriasis formation in our case. Psoriasiform dermatitis during the use of TCZ may be due to relative cytokine balance disturbance.

Acute lung injury and repair induced by single exposure of Aspergillus fumigatus in immunocompetent mice

Aim: Characterize the course of acute Aspergillus fumigatus lung infection in immunocompetent mice, investigating the immunological, pathological and tissue functional modifications. Materials & methods: C57BL/6 mice were intranasally infected with A. fumigatus conidia and euthanized to access inflammatory parameters. Results: Mice infected with A. fumigatus showed an inoculum-dependent lethality and body weight loss. An intense proinflammatory cytokine release, neutrophil infiltrate and pulmonary dysfunction was also observed in the early phase of infection. In the late phase of infection, proresolving mediators release, apoptosis and efferocytosis increased and lung tissue architecture is restored. Conclusion: Our study characterized an immunocompetent model of acute pulmonary Aspergillus infection in mice and opened an array of possibilities for investigations on interactions of A. fumigatus with host-immune system.

Understanding the Propensity for Chronic Sinusitis in Patients on Immunosuppressive Therapy

Background Chronic rhinosinusitis (CRS) is a frequently observed condition in patients with immunodeficiency secondary to immunosuppressive medications. The histologic features of CRS among patients undergoing immunosuppressive treatment have yet to be determined and may have important implications on understanding the pathophysiology of the disease process. Methods A structured histopathology report was utilized to analyze sinus tissue removed during functional endoscopic sinus surgery (FESS). Histopathology variables, Lund–Mackay score (LMS), and sinonasal outcome test 22 scores were compared among patients with CRS on immunosuppressive therapy (CRSi), CRS without nasal polyps (CRSsNP) patients, and CRS with nasal polyps (CRSwNP) patients. Results Fifteen CRSi, 36 CRSwNP, and 56 CRSsNP patients undergoing FESS were analyzed. Compared to CRSsNP, CRSi patients exhibited a trend toward increased moderate–severe inflammation (66.7% vs 42.1%, P < .080), increased neutrophil infiltrate (40.0% vs 24.6%, P < .192), and decreased fibrosis (26.7% vs 43.9%, P < .182). Compared to CRSwNP, CRSi patients demonstrated decreased fibrosis (26.7% vs 66.7%, P < .010), decreased eosinophil aggregates (13.3% vs 44.4%, P < .032), and a trend toward fewer eosinophils per high-power field (46.7% vs 66.7%, P < .154). CRSi cases had significantly lower mean LMS (8.20 ± 4.30 vs 12.78 ± 6.56, P < .017) compared to CRSwNP. Conclusion CRSi patients exhibit histopathology and disease severity more similar to CRSsNP with trends toward increased neutrophilia and reduced fibrosis. In the appropriate clinical context, discontinuing or changing a patient’s immunosuppressive regimen may be a valid treatment option in patients with CRSi. This study provides initial insight into understanding the propensity for chronic sinusitis in patients undergoing immunosuppressive treatment which may have implications on disease management.

Dysregulated neutrophil responses and neutrophil extracellular trap formation and degradation in PAPA syndrome

ObjectivesPyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome is characterised by flares of sterile arthritis with neutrophil infiltrate and the overproduction of interleukin (IL)-1β. The purpose of this study was to elucidate the potential role of neutrophil subsets and neutrophil extracellular traps (NET) in the pathogenesis of PAPA.MethodsNeutrophils and low-density granulocytes (LDG) were quantified by flow cytometry. Circulating NETs were measured by ELISA and PAPA serum was tested for the ability to degrade NETs. The capacity of NETs from PAPA neutrophils to activate macrophages was assessed. Skin biopsies were analysed for NETs and neutrophil gene signatures.ResultsCirculating LDGs are elevated in PAPA subjects. PAPA neutrophils and LDGs display enhanced NET formation compared with control neutrophils. PAPA sera exhibit impaired NET degradation and this is corrected with exogenous DNase1. Recombinant human IL-1β induces NET formation in PAPA neutrophils but not healthy control neutrophils. NET formation in healthy control neutrophils is induced by PAPA serum and this effect is inhibited by the IL-1 receptor antagonist, anakinra. NETs from PAPA neutrophils and LDGs stimulate IL-6 release in healthy control macrophages. NETs are detected in skin biopsies of patients with PAPA syndrome in association with increased tissue IL-1β, IL-8 and IL-17. Furthermore, LDG gene signatures are detected in PAPA skin.ConclusionsPAPA syndrome is characterised by an imbalance of NET formation and degradation that may enhance the half-life of these structures in vivo, promoting inflammation. Anakinra ameliorates NET formation in PAPA and this finding supports a role for IL-1 signalling in exacerbated neutrophil responses in this disease. The study also highlights other inflammatory pathways potentially pathogenic in PAPA, including IL-17 and IL-6, and these results may help guide new therapeutic approaches in this severe and often treatment-refractory condition.

Histopathology in Chronic Rhinosinusitis Varies With Sinus Culture

Background Structured histopathology reporting facilitates better understanding of the underlying pathophysiologic mechanisms of chronic rhinosinusitis. The microbiology of chronic rhinosinusitis has been studied extensively; however, distinct histopathologic changes associated with bacteria isolated in chronic rhinosinusitis are largely unknown. Objective The goal of this study is to better understand the relationship between culturable bacteria and histopathology in chronic rhinosinusitis. Methods A structured histopathology report was utilized to analyze sinus tissue removed during functional endoscopic sinus surgery in a group of patients with chronic rhinosinusitis refractory to medical therapy. Patients with cystic fibrosis or ciliary dysfunction were excluded. Histology variables included eosinophil count per high-power field, neutrophil infiltrate, basement membrane thickening, subepithelial edema, hyperplastic/papillary changes, mucosal ulceration, squamous metaplasia, fibrosis, fungal elements, Charcot-Leyden crystals, and eosinophil aggregates. Baseline Lund-Mackay score and Sinonasal Outcome Test 22 score were also collected. The association of culture data with the aforementioned variables was assessed. Results A total of 59 chronic rhinosinusitis patients who underwent functional endoscopic sinus surgery were included. Chronic rhinosinusitis patients with Pseudomonas aeruginosa had significantly increased neutrophil infiltrate (71.4% vs. 26.9%, p = 0.048), subepithelial edema (28.6% vs. 3.8%, p = 0.047), and a trend toward increased fungal elements (28.6% vs. 5.8%, p = 0.071). Chronic rhinosinusitis patients with Staphylococcus aureus had significantly more hyperplastic changes (20% vs. 2.3%, p = 0.050) and a trend toward increased squamous metaplasia (33.3% vs. 14.2%, p = 0.069). Conclusion Distinct histopathologic changes were noted based on sinus culture data for S. aureus and P. aeruginosa. These findings may have important implications on the extent of surgical management and prognosis after surgery.

Localized Juvenile Spongiotic Gingival Inflammation: A Report on 3 Cases

Background and Aims: A new pathological entity with distinct clinico-pathological features has been recently described and termed as juvenile spongiotic gingivitis. Histopathological associated features are unique and characterized by prominent intercellular edema (spongiosis) and neutrophil infiltrate. The aims of this paper were to: introduce juvenile spongiotic gingivitis to the dental and pediatric communities, to report three cases based on clinical and histopathological findings, and to discuss the most common clinical differential diagnoses. The cases were documented at baseline and follow-ups. The clinical appearance of the lesions described in this paper correspond to the pattern described by the literature: 1) localized lesions as bright red slightly raised overgrowths, most often with a subtle papillary or finely granular surface; or 2) multifocal masses or raised papular lesions with a pebbly texture. The first intention treatment approach was personal and professional plaque control. Because of the lack of a good clinical response to conventional therapy, excisional biopsies were performed, which helped establish the diagnosis. The plaque control was reinforced and additional antiseptic local treatment was administered. A real improvement in the local gingival conditions was recorded for all the patients. However, because of the persistence of some bright reddish gingival masses in one of the patients these lesions were treated by surgical excision. The overall clinical outcome was good and stable after one year. Conclusions: The presented cases might raise awareness of this condition among orthodontic specialists because orthodontic treatment could not be applied until the gingival gum disease was resolved