Coronavirus disease 2019-associated coronary endotheliitis and thrombotic microangiopathy causing cardiogenic shock: a case report.

Background: Coronavirus disease 2019 (COVID-19) primarily affects the respiratory tract but serious cardiovascular complications have been reported. Up to one-third of patients admitted to the intensive care unit may develop an acute myocardial injury, characterized by cardiac troponin elevation. However, the pathology underlying COVID-19-associated myocardial injury has rarely been reported. Case summary: Three days after being diagnosed for a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, a 52-year-old woman without a notable past medical history developed cardiogenic shock with severely reduced left ventricular ejection fraction (LVEF) at 25%. Coronary angiography was normal. Endomyocardial biopsy demonstrated coronary endotheliitis with multiple microvascular thromboses but no lymphocytic infiltrate and a negative polymerase chain reaction for SARS-CoV-2. The patient was implanted with a short-term LV assist device (Impella CP®, Abiomed, Aachen, Germany) and treated with therapeutic anticoagulation. She suffered from concomitant respiratory failure that required 14 days of orotracheal intubation, 10 days of dexamethasone, and broad-spectrum antibiotics. Clinical outcome was favourable with weaning of the Impella device after 6 days and full recovery of LVEF (65%) at 30 days. Cardiac magnetic resonance performed at Day 30 showed no evidence of myocarditis or scars and confirmed the normalization of LVEF. Discussion: This case highlights how COVID-19-associated coronary endotheliitis and thrombotic microangiopathy, in the absence of myocarditis, may induce transient severe LV dysfunction and cardiogenic shock.

Di-Tyrosine Crosslinking and NOX4 Expression as Oxidative Pathological Markers in the Lungs of Patients with Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a noninflammatory progressive lung disease. Oxidative damage is a hallmark of IPF, but the sources and consequences of oxidant generation in the lungs are unclear. In this study, we addressed the link between the H2O2-generating enzyme NADPH oxidase 4 (NOX4) and di-tyrosine (DT), an oxidative post-translational modification in IPF lungs. We performed immunohistochemical staining for DT and NOX4 in pulmonary tissue from patients with IPF and controls using validated antibodies. In the healthy lung, DT showed little or no staining and NOX4 was mostly present in normal vascular endothelium. On the other hand, both markers were detected in several cell types in the IPF patients, including vascular smooth muscle cells and epithelium (bronchial cells and epithelial cells type II). The link between NOX4 and DT was addressed in human fibroblasts deficient for NOX4 activity (mutation in the CYBA gene). Induction of NOX4 by Transforming growth factor beta 1 (TGFß1) in fibroblasts led to moderate DT staining after the addition of a heme-containing peroxidase in control cells but not in the fibroblasts deficient for NOX4 activity. Our data indicate that DT is a histological marker of IPF and that NOX4 can generate a sufficient amount of H2O2 for DT formation in vitro.

International consensus guideline for reporting transmission electron microscopy results in the diagnosis of primary ciliary dyskinesia (BEAT PCD TEM Criteria).

Primary ciliary dyskinesia (PCD) is a heterogeneous genetic condition. European and North American diagnostic guidelines recommend transmission electron microscopy (TEM) as one of a combination of tests to confirm a diagnosis. However, there is no definition of what constitutes a defect or consensus on reporting terminology. The aim of this project was to provide an internationally agreed ultrastructural classification for PCD diagnosis by TEM.A consensus guideline was developed by PCD electron microscopy experts representing 18 centres in 14 countries. An initial meeting and discussion were followed by a Delphi consensus process. The agreed guideline was then tested, modified and retested through exchange of samples and electron micrographs between the 18 diagnostic centres.The final guideline a) provides agreed terminology and a definition of Class 1 defects which are diagnostic for PCD; b) identifies Class 2 defects which can indicate a diagnosis of PCD in combination with other supporting evidence; c) describes features which should be included in a ciliary ultrastructure report to assist multidisciplinary diagnosis of PCD; and d) defines adequacy of a diagnostic sample.This tested and externally validated statement provides a clear guideline for the diagnosis of PCD by TEM which can be used to standardise diagnosis internationally.

DDR1 role in fibrosis and its pharmacological targeting.

Discoidin domain receptor1 (DDR1) is a collagen activated receptor tyrosine kinase and an attractive anti-fibrotic target. Its expression is mainly limited to epithelial cells located in several organs including skin, kidney, liver and lung. DDR1's biology is elusive, with unknown downstream activation pathways; however, it may act as a mediator of the stromal-epithelial interaction, potentially controlling the activation state of the resident quiescent fibroblasts. Increased expression of DDR1 has been documented in several types of cancer and fibrotic conditions including skin hypertrophic scars, idiopathic pulmonary fibrosis, cirrhotic liver and renal fibrosis. The present review article focuses on: a) detailing the evidence for a role of DDR1 as an anti-fibrotic target in different organs, b) clarifying DDR1 tissue distribution in healthy and diseased tissues as well as c) exploring DDR1 protective mode of action based on literature evidence and co-authors experience; d) detailing pharmacological efforts attempted to drug this subtle anti-fibrotic target to date.

Cell Spillage after Contained Electromechanical Morcellation Using a Specially Designed In-Bag System for Laparoscopic Myomectomy: Prospective Cohort Pilot Study.

STUDY OBJECTIVE: Few reports have investigated the use of endoscopic retrieval bags in the context of laparoscopic myomectomy with electromechanical morcellation. We performed a leak test of a specially designed endoscopic bag system in women undergoing laparoscopic myomectomy with contained electromechanical morcellation. DESIGN CLASSIFICATION: Prospective study. SETTING: University hospital. PATIENTS: Thirty-one women undergoing laparoscopic myomectomy with contained electromechanical morcellation. INTERVENTIONS: Electromechanical morcellation was introduced for large specimen extraction during laparoscopic procedures. Complications such as retained/disseminated parasitic tissue were documented. MEASUREMENTS AND MAIN RESULTS: Systematic peritoneal washings were performed at 3 specific times: at baseline, T1, once the peritoneal cavity was accessed laparoscopically; T2, when the myometrial incision was closed after myomectomy; and T3, after contained electromechanical morcellation. After retrieval of the endoscopic bag from the abdominal cavity, visual inspection and water test on the bag with NaCl infiltration were performed to detect leaks attributed to intraoperative perforations. A pathologist performed cytologic analyses on the 3 washings. The mean endoscopic bag procedure duration was 9 minutes. The use of a specially designed endoscopic bag system was found to be easy in 45% of cases, and no complications were reported. Cytologic washings were positive for smooth muscle cell detection in 8 cases (25.8%) at T2 and 3 cases (9.7%) at T3. All positive cases at T3 already had detectable smooth muscle cells at T2. After retrieval from the abdominal cavity, perforations on the optic access of the endoscopic bag were observed in 3 cases. CONCLUSION: The results from this pilot study are encouraging. The use of a specially designed endoscopic bag system could be an adjuvant to reduce the risk of disseminating cells during myomectomy.

[Transbronchial cryobiopsies : a minimally invasive tool for the diagnosis of interstitial lung disease]. / Cryobiopsies transbronchiques : diagnostic minimalement invasif de la fibrose pulmonaire.

The diagnosis of interstitial lung disease (ILD) is challenging and relies on a multidisciplinary discussion involving clinical, radiological and sometimes histological features. Bronchoscopic lung cryobiopsies have emerged as a new minimally invasive method of lung sampling and an alternative to surgical lung biopsies. A good diagnostic performance and excellent safety profile make it an interesting and worthful procedure which could decrease the number of patients without proper diagnosis and treatment. There is a need for further studies to standardize the technique in expert centers and to establish its role in the diagnostic work-up of ILD.

Le diagnostic des pneumopathies interstitielles (PI) est complexe et repose sur l'analyse d'éléments cliniques, radiologiques et parfois histologiques dans le cadre d'une discussion multidisciplinaire. Pour l'obtention de biopsies pulmonaires, les cryobiopsies transbronchiques constituent une nouvelle méthode minimalement invasive, alternative aux biopsies chirurgicales. Leur très bonne performance diagnostique et leur profil de sécurité favorable expliquent l'intérêt grandissant pour cette technique qui pourrait permettre de diminuer le nombre de patients n'ayant pas de diagnostic définitif établi et de traitement adapté. Des études restent encore nécessaires, au sein de centres experts, afin de standardiser les modalités pratiques de cette technique et de déterminer sa place dans l'algorithme de prise en charge des PI.

Utility of Rapid On-Site Cytologic Evaluation during Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration in Malignant and Nonmalignant Disease.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is an accurate procedure to sample mediastinal tissue. Rapid on-site cytologic evaluation (ROSE) has been advocated to improve the performance of this procedure, but its benefit remains controversial. Our objective is to assess the utility of ROSE for EBUS-TBNA diagnostic accuracy among unselected patients. METHODS: We prospectively collected data from all consecutive EBUS-TBNA procedures performed between 2008 and 2014. ROSE was introduced since 2011 in our daily practice. The accuracy of EBUS-TBNA with and without ROSE was compared in a univariate and multivariate model accounting for confounding factors. The impact of ROSE was then analyzed according to the etiology and size of the lesions. RESULTS: Among 348 EBUS-TBNA procedures analyzed, 213 were performed with ROSE. The overall accuracy tended to be better with ROSE than without (90.6 vs. 84.4%; p = 0.082). After adjustment in a multivariate model, the benefit of ROSE still did not reach statistical significance (adjusted odds ratio 1.86; 95% confidence interval 0.79-4.41). Similar results were obtained in subgroups of patients with malignant disease or sarcoidosis. The size of the lesion did not influence the impact of ROSE on accuracy. CONCLUSIONS: ROSE was associated with a moderate increase in the accuracy of EBUS-TBNA, but the difference was not statistically significant. The same effect of ROSE was observed in malignant and nonmalignant lesions and this effect was not influenced by the lesion's size.

Radiological findings of complications after lung transplantation.

Complications following lung transplantation may impede allograft function and threaten patient survival. The five main complications after lung transplantation are primary graft dysfunction, post-surgical complications, alloimmune responses, infections, and malignancy. Primary graft dysfunction, a transient ischemic/reperfusion injury, appears as a pulmonary edema in almost every patient during the first three days post-surgery. Post-surgical dysfunction could be depicted on computed tomography (CT), such as bronchial anastomosis dehiscence, bronchial stenosis and bronchomalacia, pulmonary artery stenosis, and size mismatch. Alloimmune responses represent acute rejection or chronic lung allograft dysfunction (CLAD). CLAD has three different forms (bronchiolitis obliterans syndrome, restrictive allograft syndrome, acute fibrinoid organizing pneumonia) that could be differentiated on CT. Infections are different depending on their time of occurrence. The first post-operative month is mostly associated with bacterial and fungal pathogens. From the second to sixth months, viral pneumonias and fungal and parasitic opportunistic infections are more frequent. Different patterns according to the type of infection exist on CT. Malignancy should be depicted and corresponded principally to post-transplantation lymphoproliferative disease (PTLD). In this review, we describe specific CT signs of these five main lung transplantation complications and their time of occurrence to improve diagnosis, follow-up, medical management, and to correlate these findings with pathology results. KEY POINTS: • The five main complications are primary graft dysfunction, surgical, alloimmune, infectious, and malignancy complications. • CT identifies anomalies in the setting of unspecific symptoms of lung transplantation complications. • Knowledge of the specific CT signs can allow a prompt diagnosis. • CT signs maximize the yield of bronchoscopy, transbronchial biopsy, and bronchoalveolar lavage. • Radiopathological correlation helps to understand CT signs after lung transplantation complications.

Pleomorphic Adenoma Originating from Heterotopic Salivary Tissue of the Upper Neck: A Diagnostic Pitfall.

Pleomorphic adenoma directly arising in the neck is thought to originate from heterotopic salivary gland tissue. In this article, we present the case of a 55-year-old female patient with a histologically proven pleomorphic adenoma located at the left mandibular angle, anteriorly to the sternocleidomastoid muscle and posteroinferiorly to the submandibular gland. As the patient also had an ipsilateral thyroid nodule with coarse calcifications, clinical and radiological features suggested a possible level II metastatic lymph node. However, ultrasound-guided fine needle aspiration cytology and postsurgery histopathological examination revealed a pleomorphic adenoma arising from heterotopic salivary gland tissue unrelated to a benign thyroid nodule. In this article, we provide a review of the existing literature on heterotopic salivary gland tissue and related neoplasms and discuss their imaging presentation.

User perception of endocervical sampling: A randomized comparison of endocervical evaluation with the curette vs cytobrush.

OBJECTIVES: To evaluate whether the endocervical brush (ECB) is better accepted by patients and health care providers for endocervical evaluation when compared to the endocervical curette (ECC), without a decrease in the quality of sampling. METHODS: Two hundred patients with cervical dysplasia were randomized at the colposcopy clinic of the University Hospital of Geneva into two groups according to technique. Patients and physicians' preference regarding the technique as well as the quality of samples were assessed. ECB samples were analyzed using both cytological (cell block) and histologic analysis, while ECC samples were analyzed using standard histologic analysis. RESULTS: Of the 200 patients, 89 were randomized to ECC, 101 to ECB and 10 were excluded due to incomplete information or cervical stenosis. Physicians preferred ECB against ECC, classifying it more frequently as an easy technique (94.1% vs.61.4%, p<0.001). Physicians more frequently evaluated the ECB as little or not uncomfortable for patients (28.7% vs.10.2%, p<0.001), though patients themselves didn't express a preference for either technique. From a quality standpoint, the brush allowed for a better quality of samples, with a lower rate of inadequate samples (2.0% vs 14.3%, p = 0.002) and greater amount of material. CONCLUSION: Endocervical sampling using ECB seems to be easier to perform and provides better quality samples. ECB can therefore be an acceptable alternative to ECC in standard practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT01435590.

An unusual radiologic manifestation of hypersensitivity pneumonia.

Hypersensitivity pneumonia is clinically suspected and can be characterized on computed tomography by its pattern of diffuse lung disease, in children, as in adults. However, identifying the diagnosis is not always as simple. We report an organizing pneumonia pattern of hypersensitivity pneumonia that can be seen in adult patients, but has not been reported in the pediatric population.

Evaluation of Infection Resistance of Biodegradable versus Conventional Annuloplasty Rings in an in vivo Rat Subcutaneous Model.

BACKGROUND: Biodegradable atrioventricular annuloplasty rings are theoretically more infection resistant due to their intra-annular implantation technique and nonporous structures (monofilament of poly-1,4-dioxanone). The aim of this study was to investigate the infection resistance of a biodegradable annuloplasty ring (Kalangos-Bioring®) in a rat subcutaneous implantation model and to compare it with a commonly used conventional annuloplasty ring (Edwards Physio II®). METHODS: This study included 32 Wistar albino rats which were divided into 2 groups according to the implantation of sterile or infected annuloplasty rings as control and study groups. Each animal had 2 implantation pockets (made on the right and left side of the dorsal median line) where 1 cm of the biodegradable annuloplasty ring was implanted into one pocket and 1 cm of the conventional annuloplasty ring was implanted into the other pocket. The infection model was created by topical inoculation of 1 mL Staphylococcus aureus strain (2 × 107 colony-forming units/mL) into the implantation pockets before skin closure. Each group was equally divided into 4 subgroups according to different follow-up schedules. The animals were inspected for local as well as systemic infection signs, and the rings were explanted at weeks 2, 4, 9, and 14 following implantation. Implantation pockets were evaluated macroscopically as well as by histopathological examinations. Microbiological analysis of the explanted implants with surrounding tissue was done by using quantitative sonication method. RESULTS: Conventional ring-implanted pockets showed a more prominent inflammation reaction than the biodegradable ring-implanted pockets, and this characteristic was found to be accentuated with bacterial contamination. The sterile rings did not reveal any positive cultures in either group. The number of positive cultures found in conventional rings contaminated with S. aureus was greater than in the biodegradable ring group (11/16 vs. 2/16 positive cultures, respectively; p = 0.0032). The amounts of growing bacteria in the culture environment were also statistically significantly higher in the conventional ring group (7,175 ± 5,936 vs. 181 ± 130 colony-forming units/mL, respectively; p < 0.0005). CONCLUSIONS: This is the first experimental study confirming the theoretical advantage of the infection resistance of the biodegradable annuloplasty ring (Kalangos-Bioring®) when implanted in an active infectious environment. Large animal models mimicking clinical scenarios and clinical comparative studies are needed to verify our results.

Tumor Necrosis Factor and Its Receptors Are Crucial to Control Mycobacterium bovis Bacillus Calmette-Guerin Pleural Infection in a Murine Model.

Tumor necrosis factor (TNF) is crucial to control Mycobacterium tuberculosis infection, which remains a leading cause of morbidity and mortality worldwide. TNF blockade compromises host immunity and may cause reactivation of latent infection, resulting in overt pulmonary, pleural, and extrapulmonary tuberculosis. Herein, we investigate the roles of TNF and TNF receptors in the control of Mycobacterium bovis bacillus Calmette-Guerin (BCG) pleural infection in a murine model. As controls, wild-type mice and those with a defective CCR5, a receptor that is crucial for control of viral infection but not for tuberculosis, were used. BCG-induced pleural infection was uncontrolled and progressive in absence of TNF or TNF receptor 1 (TNFR1)/TNFR2 (TNFR1R2) with increased inflammatory cell recruitment and bacterial load in the pleural cavity, and heightened levels of pleural and serum proinflammatory cytokines and chemokines, compared to wild-type control mice. The visceral pleura was thickened with chronic inflammation, which was prominent in TNF(-/-) and TNFR1R2(-/-) mice. The parietal pleural of TNF(-/-) and TNFR1R2(-/-) mice exhibited abundant inflammatory nodules containing mycobacteria, and these mice developed nonresolving inflammation and succumbed from disseminated BCG infection. By contrast, CCR5(-/-) mice survived and controlled pleural BCG infection as wild-type control mice. In conclusion, BCG-induced pleurisy was uncontrolled in the absence of TNF or TNF receptors with exacerbated inflammatory response, impaired bacterial clearance, and defective mesothelium repair, suggesting a critical role of TNF to control mycobacterial pleurisy.

BARD1 mediates TGF-ß signaling in pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a rapid progressive fibro-proliferative disorder with poor prognosis similar to lung cancer. The pathogenesis of IPF is uncertain, but loss of epithelial cells and fibroblast proliferation are thought to be central processes. Previous reports have shown that BARD1 expression is upregulated in response to hypoxia and associated with TGF-ß signaling, both recognized factors driving lung fibrosis. Differentially spliced BARD1 isoforms, in particular BARD1ß, are oncogenic drivers of proliferation in cancers of various origins. We therefore hypothesized that BARD1 and/or its isoforms might play a role in lung fibrosis. METHODS: We investigated BARD1 expression as a function of TGF-ß in cultured cells, in mice with experimentally induced lung fibrosis, and in lung biopsies from pulmonary fibrosis patients. RESULTS: FL BARD1 and BARD1ß were upregulated in response to TGF-ß in epithelial cells and fibroblasts in vitro and in vivo. Protein and mRNA expression studies showed very low expression in healthy lung tissues, but upregulated expression of full length (FL) BARD1 and BARD1ß in fibrotic tissues. CONCLUSION: Our data suggest that FL BARD1 and BARD1ß might be mediators of pleiotropic effects of TGF-ß. In particular BARD1ß might be a driver of proliferation and of pulmonary fibrosis pathogenesis and progression and represent a target for treatment.

Human papillomavirus genotype distribution among Cameroonian women with invasive cervical cancer: a retrospective study.

OBJECTIVES: We determined the human papillomavirus (HPV) types present in invasive cervical cancer (ICC) of women in Cameroon in order to estimate the potential efficacies of HPV prophylactic vaccines. METHODS: This is a retrospective study using 181 formalin-fixed paraffin-embedded cervical tissue samples of ICC collected from the Institute of Pathology, Gyneco-Obstetric and Pediatric Hospital, Yaoundé, Cameroon. HPV was detected by PCR using modified GP5+/GP6+ (MGP) primers. Genotyping was performed by reverse-blot hybridisation, which allowed the detection of 9 of the 14 high-risk HPV types. RESULTS: Of the 181 samples, 91.7% were squamous cell carcinomas and 6.6% were adenocarcinomas. Counting all the single and multiple infections, the three most common high-risk types in descending order were HPV16 (88%), HPV45 (32%) and HPV18 (14.8%). 54.9% of cases were infected with a single HPV type and 45.1% had two or more HPV infections. CONCLUSIONS: The frequencies of HPV16, HPV45 and multiple infections are all higher than previously reported. These observations have significant implications on the consideration of vaccination strategies because each vaccine has different duration and efficacies in cross-protection of different HPV types. The method used proved to be sensitive and cost-efficient for retrospective studies where fresh materials are not available.

Macrophage-specific NOX2 contributes to the development of lung emphysema through modulation of SIRT1/MMP-9 pathways.

Reactive oxygen species (ROS) participate in the pathogenesis of emphysema. Among ROS-producing enzymes, NOX NADPH oxidases are thought to be responsible for tissue injury associated with several lung pathologies. To determine whether NOX2 and/or NOX1 participate in the development of emphysema, their expression patterns were first studied by immunohistochemistry in the lungs of emphysematous patients. Subsequently, we investigated their contribution to elastase-induced emphysema using NOX2- and NOX1-deficient mice. In human lung, NOX2 was mainly detected in macrophages of control and emphysematous lungs, while NOX1 was expressed in alveolar epithelium and bronchial cells. We observed an elevated number of NOX2-positive cells in human emphysematous lungs, as well as increased NOX2 and NOX1 mRNA expression in mouse lungs following elastase exposure. Elastase-induced alveolar airspace enlargement and elastin degradation were prevented in NOX2-deficient mice, but not in NOX1-deficient mice. This protection was independent of inflammation and correlated with reduced ROS production. Concomitantly, an elevation of sirtuin 1 (SIRT1) level and a decrease of matrix metalloproteinase-9 (MMP-9) expression and activity were observed in alveolar macrophages and neutrophils. We addressed the specific role of macrophage-restricted functional NOX2 in elastase-induced lung emphysema using Ncf1 mutant mice and Ncf1 macrophage rescue mice (Ncf1 mutant mice with transgenic expression of Ncf1 only in CD68-positive mononuclear phagocytes; the MN mouse). Compared to WT mice, the lack of functional NOX2 led to decreased elastase-induced ROS production and protected against emphysema. In contrast, ROS production was restored specifically in macrophages from Ncf1 rescue mice and contributes to emphysema. Taken together, our results demonstrate that NOX2 is involved in the pathogenesis of human emphysema and macrophage-specific NOX2 participates in elastase-induced emphysema through the involvement of SIRT1/MMP-9 pathways in mice.

Bacillus calmette-guerin infection in NADPH oxidase deficiency: defective mycobacterial sequestration and granuloma formation.

Patients with chronic granulomatous disease (CGD) lack generation of reactive oxygen species (ROS) through the phagocyte NADPH oxidase NOX2. CGD is an immune deficiency that leads to frequent infections with certain pathogens; this is well documented for S. aureus and A. fumigatus, but less clear for mycobacteria. We therefore performed an extensive literature search which yielded 297 cases of CGD patients with mycobacterial infections; M. bovis BCG was most commonly described (74%). The relationship between NOX2 deficiency and BCG infection however has never been studied in a mouse model. We therefore investigated BCG infection in three different mouse models of CGD: Ncf1 mutants in two different genetic backgrounds and Cybb knock-out mice. In addition, we investigated a macrophage-specific rescue (transgenic expression of Ncf1 under the control of the CD68 promoter). Wild-type mice did not develop severe disease upon BCG injection. In contrast, all three types of CGD mice were highly susceptible to BCG, as witnessed by a severe weight loss, development of hemorrhagic pneumonia, and a high mortality (∼ 50%). Rescue of NOX2 activity in macrophages restored BCG resistance, similar as seen in wild-type mice. Granulomas from mycobacteria-infected wild-type mice generated ROS, while granulomas from CGD mice did not. Bacterial load in CGD mice was only moderately increased, suggesting that it was not crucial for the observed phenotype. CGD mice responded with massively enhanced cytokine release (TNF-α, IFN-γ, IL-17 and IL-12) early after BCG infection, which might account for severity of the disease. Finally, in wild-type mice, macrophages formed clusters and restricted mycobacteria to granulomas, while macrophages and mycobacteria were diffusely distributed in lung tissue from CGD mice. Our results demonstrate that lack of the NADPH oxidase leads to a markedly increased severity of BCG infection through mechanisms including increased cytokine production and impaired granuloma formation.

Prevention of hyperoxia-induced bronchial hyperreactivity by sildenafil and vasoactive intestinal peptide: impact of preserved lung function and structure.

OBJECTIVE: Hyperoxia exposure leads to the development of lung injury and bronchial hyperreactivity (BHR) via involvement of nitric oxide (NO) pathway. We aimed at characterizing whether the stimulation of the NO pathway by sildenafil or vasoactive intestinal peptide (VIP) is able to prevent the hyperoxia-induced development of BHR. The respective roles of the preserved lung volume and alveolar architecture, the anti-inflammatory and anti-apoptotic potentials of these treatments in the diminished lung responsiveness were also characterized. MATERIALS AND METHODS: Immature (28-day-old) rats were exposed for 72 hours to room air (Group C), hyperoxia (>95%, Group HC), or hyperoxia with the concomitant administration of vasoactive intestinal peptide (VIP, Group HV) or sildenafil (Group HS). Following exposure, the end-expiratory lung volume (EELV) was assessed plethysmographically. Airway and respiratory tissue mechanics were measured under baseline conditions and following incremental doses of methacholine to assess BHR. Inflammation was assessed by analyzing the bronchoalveolar lavage fluid (BALF), while biochemical and histological analyses were used to characterize the apoptotic and structural changes in the lungs. RESULTS: The BHR, the increased EELV, the aberrant alveolarization, and the infiltration of inflammatory cells into the BALF that developed in Group HC were all suppressed significantly by VIP or sildenafil treatment. The number of apoptotic cells increased significantly in Group HC, with no evidence of statistically significant effects on this adverse change in Groups HS and HV. CONCLUSIONS: These findings suggest that stimulating the NO pathway by sildenafil and VIP exert their beneficial effect against hyperoxia-induced BHR via preserving normal EELV, inhibiting airway inflammation and preserving the physiological lung structure, whereas the antiapoptotic potential of these treatments were not apparent in this process.

NOX1 is responsible for cell death through STAT3 activation in hyperoxia and is associated with the pathogenesis of acute respiratory distress syndrome.

Reactive oxygen species (ROS) contribute to alveolar cell death in acute respiratory distress syndrome (ARDS) and we previously demonstrated that NOX1-derived ROS contributed to hyperoxia-induced alveolar cell death in mice. The study investigates whether NOX1 expression is modulated in epithelial cells concomitantly to cell death and associated to STAT3 signaling in the exudative phase of ARDS. In addition, the role of STAT3 activation in NOX1-dependent epithelial cell death was confirmed by using a lung epithelial cell line and in mice exposed to hyperoxia. NOX1 expression, cell death and STAT3 staining were evaluated in the lungs of control and ARDS patients by immunohistochemistry. In parallel, a stable NOX1-silenced murine epithelial cell line (MLE12) and NOX1-deficient mice were used to characterize signalling pathways. In the present study, we show that NOX1 is detected in alveolar epithelial cells of ARDS patients in the exudative stage. In addition, increased alveolar epithelial cell death and phosphorylated STAT3 are observed in ARDS patients and associated with NOX1 expression. Phosphorylated STAT3 is also correlated with TUNEL staining. We also confirmed that NOX1-dependent STAT3 activation participates to alveolar epithelial cell death. Silencing and acute inhibition of NOX1 in MLE12 led to decreased cell death and cleaved-caspase 3 induced by hyperoxia. Additionally, hyperoxia-induced STAT3 phosphorylation is dependent on NOX1 expression and associated with cell death in MLE12 and mice. This study demonstrates that NOX1 is involved in human ARDS pathophysiology and is responsible for the damage occurring in alveolar epithelial cells at least in part via STAT3 signalling pathways.