Hyperplastic Type Research Articles

Overdiagnosing giant bullous emphysema as metastatic adenocarcinoma: a case report

BackgroundGiant bullous emphysema is characterized by large bullae occupying at least one-third of the hemithorax and leading to compression of the surrounding lung parenchyma. Overdiagnosis can occur because of the atypical appearance of hyperplastic type II pneumocytes, which may be mistaken for malignant cells.Case presentationA 48-year-old male with a history of smoking and occupational exposure presented with dyspnea and drowsiness. Initial chest X-ray revealed a tension pneumothorax, and subsequent chest CT revealed extensive bullous emphysema and lung cancer in the right middle lobe (RML). Pathologic examination initially indicated resected bullae to metastatic adenocarcinoma, but upon review, it was determined that the reactive alveolar cells were misdiagnosed as malignant.ConclusionsThis case emphasizes the need for thorough histopathological assessment and prudent interpretation of atypical cellular morphology.

Genotype-histotype-phenotype correlations in hyperinsulinemic hypoglycemia.

Hyperinsulinemic hypoglycemia (HH) of pancreatic origin includes congenital hyperinsulinism (CHI), insulinoma, insulinomatosis, and adult-onset non-insulinoma persistent hyperinsulinemic hypoglycemia syndrome (NI-PHHS). In this review, we describe the genotype-histotype-phenotype correlations in HH and their therapeutic implications. CHI can occur from birth or later on in life. Histologically, diffuse CHI shows diffuse beta cell hypertrophy with a few giant nuclei per islet of Langerhans, most frequently caused by loss-of-function mutations in ABCC8 or KCNJ11. Focal CHI is histologically characterized by focal adenomatous hyperplasia consisting of confluent hyperplastic islets, caused by a paternal ABCC8/KCNJ11 mutation combined with paternal uniparental disomy of 11p15. CHI in Beckwith-Wiedemann syndrome is caused by mosaic changes in the imprinting region 11p15.4-11p15.5, leading to segmental or diffuse overgrowth of endocrine tissue in the pancreas. Morphological mosaicism of pancreatic islets is characterized by occurence of hyperplastic (type 1) islets in one or a few lobules and small (type 2) islets in the entire pancreas. Other rare genetic causes of CHI show less characteristic or unspecific histology. HH with a predominant adult onset includes insulinomas, which are pancreatic insulin-producing endocrine neoplasms, in some cases with metastatic potential. Insulinomas occur sporadically or as part of multiple endocrine neoplasia type 1 due to MEN1 mutations. MAFA mutations may histologically lead to insulinomatosis with insulin-producing neuroendocrine microadenomas or neuroendocrine neoplasms. NI-PHHS is mainly seen in adults and shows slight histological changes in some patients, which have been defined as major and minor criteria. The genetic cause is unknown in most cases. The diagnosis of HH, as defined by genetic, histological, and phenotypic features, has important implications for patient management and outcome.

Understanding the Pathogenesis of Red Mark Syndrome in Rainbow Trout (Oncorhynchus mykiss) through an Integrated Morphological and Molecular Approach.

Red mark syndrome (RMS) is a widespread skin disorder of rainbow trout in freshwater aquaculture, believed to be caused by a Midichloria-like organism (MLO). Here, we aimed to study the pathologic mechanisms at the origin of RMS by analyzing field samples from a recent outbreak through gene expression, MLO PCR, quantitative PCR, and a histopathological scoring system proposed for RMS lesions. Statistical analyses included a One-Way Analysis of Variance (ANOVA) with a Dunnett's multiple comparisons test to assess differences among gene expression groups and a nonparametric Spearman correlation between various categories of skin lesions and PCR results. In short, the results confirmed the presence of a high quantity of 16S gene copy numbers of Midichloria-like organisms in diseased skin tissues. However, the number of Midichloria-like organisms detected was not correlated to the degree of severity of skin disease. Midichloria-like organism DNA was found in the spleen and head kidney. The spleen showed pathologic changes mainly of hyperplastic type, reflecting its direct involvement during infection. The most severe skin lesions were characterized by a high level of inflammatory cytokines sustaining and modulating the severe inflammatory process. IL-1 β, IL-6, IL-10, MHC-II, and TCR were upregulated in severe skin lesions, while IL-10 was highly expressed in moderate to severe ones. In the moderate form, the response was driven to produce immunoglobulins, which appeared crucial in controlling the skin disease's severity. Altogether our results illustrated a complex immune interaction between the host and Midichloria-like organism.

A Subset of Salivary Intercalated Duct Lesions Harbors Recurrent CTNNB1 and HRAS Mutations: A Molecular Link to Basal Cell Adenoma and Epithelial-Myoepithelial Carcinoma?

Intercalated duct lesions (IDLs) are benign salivary gland proliferations that resemble normal intercalated ducts and are subdivided into hyperplastic, adenoma or hybrid types depending on circumscription. While IDLs were historically regarded as non-neoplastic, frequent association with basal cell adenoma (BCA) and epithelial-myoepithelial carcinoma (EMC) has raised the possibility that they are neoplastic precursors. In this study, we performed β-catenin immunohistochemistry and targeted molecular analysis on IDLs to clarify their pathogenesis. We identified 15 IDLs from the parotid glands of eight men and six women with a median age of 65years (range 42-85years). These lesions included nine hyperplastic, three adenoma, and three hybrid types. Nuclear β-catenin localization was present in 7 of 13 lesions tested (54%). Next generation sequencing was successfully completed in 12 IDLs, of which seven (58%) had likely oncogenic mutations. These included three recurrent CTNNB1 mutations in hyperplastic (n = 2) and hybrid (n = 1) lesions and two recurrent HRAS hotspot mutations in adenomas. Despite substantial heterogeneity, these findings confirm that a majority of IDLs are genuinely neoplastic, and some demonstrate molecular overlap with both BCA and EMC, supporting their theorized role as precursors to these tumors. Nevertheless, no oncogenic drivers were present in a significant subset of cases, suggesting that some IDLs may be truly reactive and hyperplastic. As such, IDL appear to represent a diverse morphologic and molecular spectrum that include both neoplastic and hyperplastic lesions. Reconsideration of the boundary between IDL and BCA in the future may be necessary to simplify classification.

Pneumopatia tóxica por Trema micrantha em ovinos no Estado de Santa Catarina, Brasil

ABSTRACT: Poisoning by Trema micrantha commonly causes hepatocellular necrosis in cattle, sheep, and goats and edema and cerebral hemorrhage in horses. This plant can cause toxic pneumopathy in sheep, and there is only one report of the natural form and one of the experimental form in the State of Rio Grande do Sul. This study aimed to report an outbreak of the respiratory form of natural poisoning by T. micrantha in sheep. Six sheep developed clinical respiratory signs after consumption of the plant and four of them died and two recovered after treatment with dexamethasone. The sheep presented tachypnea, noisy breathing, edema of the face, eyelids, and vulva, and subcutaneous emphysema on the face and neck. Necropsy (Sheep 2, 3, and 4) showed uncollapsed, heavy, diffuse red lungs with evident costal impressions and a moderate amount of serosanguineous fluid flowed at section. The liver had a moderate diffuse evident lobular pattern. The histopathology of the lungs of the three necropsied sheep showed congestion and edema with the formation of hyaline membranes within accentuated diffuse alveoli, in addition to thickening of the alveolar septa due to mild to moderate diffuse type II pneumocyte hyperplasia and also mild to moderate diffuse infiltrate of macrophages, lymphocytes, plasma cells, and neutrophils in the lumen of alveoli, bronchi, and bronchioles. Sheep 3 also showed type II pneumocytes with enlarged and hyperchromatic nuclei, sometimes binucleated with evident nucleoli, and, in some regions, the pneumocytes were desquamated to the alveolar lumen forming small syncytia and mild multifocal hyperplasia in the bronchial epithelium. The anti-cytokeratin IHC evaluation showed marked diffuse intracytoplasmic staining in hyperplastic type II pneumocytes in the bronchiolar epithelium of the three evaluated sheep. The liver of the three sheep had mild multifocal centrilobular necrosis. It seems to be the second report of spontaneous poisoning by T. micrantha in sheep developing lung lesions described in Brazil and the first in the State of Santa Catarina.

MUC16 Is Overexpressed in Idiopathic Pulmonary Fibrosis and Induces Fibrotic Responses Mediated by Transforming Growth Factor-β1 Canonical Pathway

Several transmembrane mucins have demonstrated that they contribute intracellularly to induce fibrotic processes. The extracellular domain of MUC16 is considered as a biomarker for disease progression and death in IPF patients. However, there is no evidence regarding the signalling capabilities of MUC16 that contribute to IPF development. Here, we demonstrate that MUC16 was overexpressed in the lung tissue of IPF patients (n = 20) compared with healthy subjects (n = 17) and localised in fibroblasts and hyperplastic alveolar type II cells. Repression of MUC16 expression by siRNA-MUC16 transfection inhibited the TGF-β1-induced fibrotic processes such as mesenchymal/ myofibroblast transformations of alveolar type II A549 cells and lung fibroblasts, as well as fibroblast proliferation. SiRNA-MUC16 transfection also decreased the TGF-β1-induced SMAD3 phosphorylation, thus inhibiting the Smad Binding Element activation. Immunoprecipitation assays and confocal immunofluorescence showed the formation of a protein complex between MUC16/p-SMAD3 in the cell membrane after TGF-β1 stimulation. This study shows that MUC16 is overexpressed in IPF and collaborates with the TGF-β1 canonical pathway to induce fibrotic processes. Therefore, direct or indirect targeting of MUC16 could be a potential drug target for human IPF.

Hermansky-Pudlak syndrome pulmonary fibrosis: a rare inherited interstitial lung disease.

Pulmonary fibrosis is a progressive interstitial lung disease of unknown aetiology with a poor prognosis. Studying genetic diseases associated with pulmonary fibrosis provides insights into the pathogenesis of the disease. Hermansky-Pudlak syndrome (HPS), a rare autosomal recessive disorder characterised by abnormal biogenesis of lysosome-related organelles, manifests with oculocutaneous albinism and excessive bleeding of variable severity. Pulmonary fibrosis is highly prevalent in three out of 10 genetic types of HPS (HPS-1, HPS-2 and HPS-4). Thus, genotyping of individuals with HPS is clinically relevant. HPS-1 tends to affect Puerto Rican individuals due to a genetic founder effect. HPS pulmonary fibrosis shares some clinical features with idiopathic pulmonary fibrosis (IPF), including dyspnoea, cough, restrictive lung physiology and computed tomography (CT) findings of fibrosis. In contrast to IPF, HPS pulmonary fibrosis generally affects children (HPS-2) or middle-aged adults (HPS-1 or HPS-4) and may be associated with ground-glass opacification in CT scans. Histopathology of HPS pulmonary fibrosis, and not IPF, shows vacuolated hyperplastic type II cells with enlarged lamellar bodies and alveolar macrophages with lipofuscin-like deposits. Antifibrotic drugs approved as treatment for IPF are not approved for HPS pulmonary fibrosis. However, lung transplantation has been performed in patients with severe HPS pulmonary fibrosis. HPS pulmonary fibrosis serves as a model for studying fibrotic lung disease and fibrosis in general.

Rehabilitation and clinical-evolutive aspects in a case of paraparesis after multilevel lumbar disc herniation, spinal canal stenosis and spondylolisthesis iteratively operated, in a pluripathological context

Introduction. Disc herniation occurs most commonly in the lumbar region (95% of the cases). The current trend is to have surgery on patients with disc herniation if the kinetic treatment was not beneficial. The data from the literature suggest that early active recovery after lumbar disc herniation is more beneficial than a traditional, less active training program. Material and method. Having the patient's consent and the approval of the Ethics Committee of “Bagdasar-Arseni” Clinical Emergency Hospital, N.O. 17464 / 14.06.2019, the paper presents the case of a 75-year-old patient with paraparesis after multilevel lumbar disc herniation, spinal canal stenosis and spondylolisthesis iteratively operated, in pluripathological context (hyperplastic type II obesity, hypertension, prostate adenocarcinoma operated in 2015, Clostridium enterocolitis). The patient was clinically and functionally evaluated, according to the standardized protocols implemented in our clinic, through the assessment scales (ASIA, FIM, FAC, QoL, Ashworth and Penn) and also paraclinically, in order to evaluate his biological reserve and his bearing availability of the recovery program. Results and discussions. The patient presented a slowly favorable evolution (slowed down not only by his multiple above-mentioned comorbidities) from a dysfunctional point of view. Conclusions. Early active recovery after lumbar disc herniation surgery is more beneficial than a traditional, less active training program for operated herniated discs. Keywords: Schizophrenia, spinal cord injury, multidisciplinary, suicide attempt, rehabilitation,

MUC4 is overexpressed in idiopathic pulmonary fibrosis and collaborates with transforming growth factor β inducing fibrotic responses.

Several mucins are implicated in idiopathic pulmonary fibrosis (IPF); however, there is no evidence regarding the role of MUC4 in the development of IPF. Here we demonstrated that MUC4 was overexpressed in IPF patients (n = 22) compared with healthy subjects (n = 21) and located in pulmonary arteries, bronchial epithelial cells, fibroblasts, and hyperplastic alveolar type II cells. Decreased expression of MUC4 using siRNA-MUC4 inhibited the mesenchymal/myofibroblast transformations of alveolar type II A549 cells and lung fibroblasts, as well as cell senescence and fibroblast proliferation induced by TGF-β1. The induction of the overexpression of MUC4 increased the effects of TGF-β1 on mesenchymal/myofibroblast transformations and cell senescence. MUC4 overexpression and siRNA-MUC4 gene silencing increased or decreased, respectively, the phosphorylation of TGFβRI and SMAD3, contributing to smad-binding element activation. Immunoprecipitation analysis and confocal immunofluorescence showed the formation of a protein complex between MUC4β/p-TGFβRI and p-SMAD3 in the cell membrane after TGF-β1 stimulation and in lung tissue from IPF patients. Bleomycin-induced lung fibrosis was reduced in mice transiently transfected with siRNA-MUC4. This study shows that MUC4 expression is enhanced in IPF and promotes fibrotic processes in collaboration with TGF-β1 canonical pathway that could be an attractive druggable target for human IPF.

Malignant transformation in oral lichen planus and lichenoid lesions: a 14-year longitudinal retrospective cohort study of 829 patients in New Zealand

The aim of this study was to identify the rate of malignant transformation in a longitudinal cohort of patients with oral lichen planus and oral lichenoid lesion (OLP/OLL) and to assess the associations between clinicopathologic aspects and malignant transformation. Data were taken from the records of 829 patients histologically diagnosed with OLP/OLL in the years 2005 to 2018. Of the study patients, 548 (66.1%) were females and 281 (33.9%) were males. The average age at diagnosis was 57.3 years. The hyperplastic type was the most frequent (58.5%). Most patients had multiple sites of involvement, with the buccal mucosa being the most frequent site of biopsy. Oral epithelial dysplasia developed in 5 (0.6%) patients with a previous histologic diagnosis of OLP/OLL and developed oral squamous cell carcinoma (OSCC) in 23 patients (2.8%) during the follow-up period. The atrophic/ulcerative forms are 25.8 times more likely to progress to OSCC compared with the hyperplastic types (hazard ratio [HR] 25.8; P < .05). The HR increases by 5% with every year of age (HR 1.05; 95% confidence interval; P < .05). In our study, oral epithelial dysplasia developed in less than 1% of patients with OLP/OLL, and OSCC in 2.8%during the follow-up period. The atrophic/ulcerative forms are 25.8 times more likely to progress to OSCC compared with the hyperplastic types. The HR increases by 5% with every year of age.

The Effect of Nanostructured Hydroxyapatite Coating on Distraction Osteogenesis

Dogs underwent high-frequency automated tibia lengthening with the Ilizarov apparatus over a 1.8-mm hydroxyapatite-coated intramedullary titanium wire. Daily distraction was 3.0 mm with a fraction of 0.125 mm/h and continued ten days. The regenerate was well vascularized, had zonal structure and was of normal or hyperplastic type to the end of distraction. Osteogenesis was fast and complete. The wire served for both mechanical and biological reinforcement of the bone callus and provided reduction of external fixation time. Mean consolidation time with the apparatus on the limb was 13.83±4.02 days. Overall, external fixation index was 10.5 days/cm and 4.8 days/cm in the consolidation phase.

MUC1 intracellular bioactivation mediates lung fibrosis

BackgroundSerum KL6/mucin 1 (MUC1) has been identified as a potential biomarker in idiopathic pulmonary fibrosis (IPF), but the role of MUC1 intracellular bioactivation in IPF is unknown.ObjectiveTo characterise MUC1 intracellular...

The Oncogene ECT2 Contributes to a Hyperplastic, Proliferative Lung Epithelial Cell Phenotype in Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) and lung cancer are progressive lung diseases with a poor prognosis. IPF is a risk factor for the development of lung cancer, and the incidence of lung cancer is increased in patients with IPF. The disease pathogenesis of IPF and lung cancer involves common genetic alterations, dysregulated pathways, and the emergence of hyperplastic and metaplastic epithelial cells. Here, we aimed to identify novel, common mediators that might contribute to epithelial cell reprogramming in IPF. Gene set enrichment analysis of publicly available non-small cell lung cancer and IPF datasets revealed a common pattern of misregulated genes linked to cell proliferation and transformation. The oncogene ECT2 (epithelial cell transforming sequence 2), a guanine nucleotide exchange factor for Rho GTPases, was highly enriched in both IPF and non-small cell lung cancer compared with nondiseased controls. Increased expression of ECT2 was verified by qPCR and Western blotting in bleomycin-induced lung fibrosis and human IPF tissue. Immunohistochemistry demonstrated strong expression of ECT2 staining in hyperplastic alveolar epithelial type II (ATII) cells in IPF, as well as its colocalization with proliferating cell nuclear antigen, a well-known proliferation marker. Increased ECT2 expression coincided with enhanced proliferation of primary mouse ATII cells as analyzed by flow cytometry. ECT2 knockdown in ATII cells resulted in decreased proliferation and collagen I expression in vitro. These data suggest that the oncogene ECT2 contributes to epithelial cell reprogramming in IPF, and further emphasize the hyperplastic, proliferative ATII cell as a potential target in patients with IPF and lung cancer.

Pathological Study on Epithelial-Mesenchymal Transition in Silicotic Lung Lesions in Rat

Silicosis, caused by the inhalation of crystalline silicon dioxide or silica, is one of the most severe occupational diseases. Persistent inflammation and progressive massive pulmonary fibrosis are the most common histological changes caused by silicosis. Association of epithelial-mesenchymal transition (EMT) of hyperplastic type II epithelial cells with the fibrotic events of pulmonary fibrosis has been suggested in in vitro silica-exposed cultured cell models, patients with idiopathic pulmonary fibrosis, and bleomycin-induced experimental models. Histological features of EMT, however, are not fully described in silicotic lungs in in vivo. The purpose of this study was to demonstrate EMT of hyperplastic type II epithelial cells in the developmental process of progressive massive pulmonary fibrosis in the lungs of rats exposed to silica. F344 female rats were intratracheally instilled with 20 mg of crystalline silica (Min-U-Sil-5), followed by sacrifice at 1, 3, 6, and 12 months after instillation. Fibrosis, characterized by the formation of silicotic nodules, progressive massive fibrosis, and diffuse interstitial fibrosis, was observed in the lungs of the treated rats; the effects of fibrosis intensified in a time-dependent manner. Hyperplasia of the type II epithelial cells, observed in the massive fibrotic lesions, dominated in the lungs of rats at 6 and 12 months after the treatment. Immunohistochemistry of the serial sections of the lung tissues demonstrated positive labeling for cytokeratin, vimentin, and α-smooth muscle actin in spindle cells close to the foci of hyperplasia of type II epithelial cells. Spindle cells, which exhibited features of both epithelial cells and fibroblasts, were also demonstrated with bundles of collagen fibers in the fibrotic lesions, using electron microscopy. Increased expression of TGF-β was shown by Western blotting and immunohistochemistry in the lungs of the treated rats. These findings suggested that enhanced TGF-β expression and EMT of hyperplastic type II epithelial cells are involved in the development process of progressive massive pulmonary fibrosis during silicosis.

PULMONARY-RENAL SYNDROME: DIFFICULTIES OF DIFFERENTIAL DIAGNOSIS

The study objective is to demonstrate the difficulty of differential diagnosis in pulmonary-renal syndrome using a clinical case as an example.Materials and methods. Male patient A., 68 years old, retired, was hospitalized at the N.I. Pirogov City Clinical Hospital № 1 in December of 2017 with complaints of inefficient cough, fever of 39 °С, weakness, apnea, weight loss up 10 kg in 3 months. Examination revealed skin and mucosa paleness, calf edema, heart beat of 102 bpm, normal rhythm, arterial pressure 130/80 mm Hg, respiratory rate 22 breaths per min. Auscultation revealed harsh respiration in the lungs, weakened in the lower parts, fine moist rales. Anemia (hemoglobin – 53 g/l, erythrocytes – 1.85 × 1012/l, serum iron – 3.1 µmol/l), elevated urea up to 41.4 mmol/l, creatinine up to 843.1 µmol/l (glomerular filtration rate – 6 ml/min/1.73 m2), leukocytes up to 12.5 × 109/l, С-reactive protein up to 124.96 mg/l were diagnosed. Clinical urine analysis showed proteinuria 0.47 g/l. Computed tomography of the chest revealed pronounced infiltrative changes in tissues of both lungs, more on the right, alveolitis, bronchiolitis in the middle lobe on the right, 5th segment on the left. Lymphadenopathy mediastinal was diagnosed. After examination (multiple bacteriological blood, sputum tests, interferon-gamma release assay, echocardiography, bronchoalveolar lavage, sterna puncture, esophagogastroduodenoscopy, colonoscopy, etc.), oncological pathology, tuberculosis of the lungs, sepsis, infections endocarditis and other infectious pathologies were excluded. Antibacterial courses prescribed earlier were ineffective. Immunological blood test revealed high titers (1:1280) of antineutrophil cytoplasmic antibodies (ANCA) with perinuclear fluorescence type (myeloperoxidase specificity), negative antibodies to glomerular basal membrane which allowed to diagnose ANCA-associated vasculitis.Results. Considering the data of clinical, lab, and instrumental examination, the patient was diagnosed with microscopic polyangiitis, ANCA-associated, affecting the lungs (disseminated interstitial lung disease with bronchiolitis) and kidneys (rapidly progressive glomerulonephritis), intrathoracic lymphadenopathy, activity grade III (BVAS index – 23 points). Grade II respiratory failure. Chronic kidney disease 5D (glomerular filtration rate – 6 ml/min/1.73 m2). Grade II arterial hypertension, risk 4. Grade II pulmonary hypertension. Chronic heart failure 2А, functional class IV. Mixed anemia (iron-deficient, chronic disease), severe. Disseminated polyposis of the colon (hyperplastic type). At the hospital, antibacterial drugs (cefoperazone sulbactam), antifungal (fluticasone) were administered, anemia was corrected (iron-containing drugs and erythropoietin, hemotransfusion), hemodialysis. Cyclophosphane 400 mg was administered intravenously, a week later – 800 mg. Methylprednisolone (60 mg/day), co-trimoxazole (480 mg 3 times a week) were prescribed. A pronounced improvement was observed due to the therapy: body temperature normalization, decreased apnea, cough, weakness, increased appetite. The patient was discharged with recommendation for continuation of cytostatic therapy per the regimen and prescription for programmed hemodialysis at the place of residence.Conclusion.This clinical case demonstrates a necessity of considering ANCA-associated vasculitis during differential diagnosis of pulmonary-renal syndrome. Timely diagnosis and active cytostatic therapy play a principal role in treatment and promote deceleration of disease progression and improve prognosis.

23 - Control of protein cysteine oxidation in lung fibrosis via a coordinated network of protein disulfide oxidoreductases

Pulmonary fibrosis (IPF) is a devastating progressive disease that is fatal within 3-5 years of diagnosis. We recently demonstrated increases in protein S-glutathionylation (PSSG) in lungs from patients with IPF which correlated with loss of lung function (Anathy, Nature Medicine 2018). We have also shown that PSSG in lung epithelial cells is controlled by glutaredoxin (GLRX) glutathione S-transferase P (GSTP), and protein disulfide isomerase A3 (PDIA3). Assessment of transcripts of these oxidoreductases in IPF lung tissues and controls revealed small but statistically significant increases in mRNA levels of PDIA3, whereas expression of GSTPand GLRXmRNAs was unchanged in IPF patients compared to controls. Despite the lack of GSTPmRNA expression changes in IPF, we have observed robust expression of GSTP in hyperplastic type II epithelial cells and in regions of disease progression in IPF.Pharmacological inhibition of GSTP, using TLK117, a clinically applicable inhibitor of GSTP, protected against the progression of bleomycin-induced fibrosis in association with decreased S-glutathionylation (McMillan JCI Insight 2016). Despite slight changes in GLRXmRNA, GLRX enzymatic activity was strongly attenuated in lungs from patients with IPF. Administration of recombinant active Glrx to mice with pre-existing bleomycin or TGFB1-induced fibrosis reversed the existing increases in fibrosis in association with decreased S-glutathionylation. Similarly, epithelial specific ablation of Pdia3, or pharmacological inhibition of PDIs also attenuated bleomycin-induced lung epithelial apoptosis and fibrosis in mice. Collectively these findings suggest that multiple redox enzymes (PDIA3, GSTP, GLRX) act in concert to control the extent of S-glutathionylation, apoptosis and fibrogenesis. Coordinated targeting of this enzyme axis may provide a powerful strategy to restore redox homeostasis and reverse fibrosis. Our findings also indicate that global transcriptomics analyses in lung tissue homogenates may not identify relevant targets for pharmacological manipulation, given that PDIA3, GSTP, and GLRX activities, were found be a strong determinants of disease progression, instead of mRNA expression.

Prevalence and risk factors for fundic gland polyps

The incidence of fundic gland polyps (FGPs) is increasing rapidly and has surpassed hyperplastic polyps to become the most common epithelial gastric polyps in Western countries and China.1, 2 They are usually multiple, small (1-5 mm), transparent, and sessile; the background gastric mucosa is typically normal.3 FGPs are more prevalent among females and are often located in the gastric fundus and body. There are two types of FGPs: sporadic and syndromic (in association with familial adenomatosis polyposis). Although different in their genetic and molecular backgrounds, sporadic and syndromic FGPs are histologically and histochemically indistinguishable. Syndromic FGPs occur in the presence of inherited germline mutation in the adenomatous polyposis coli (APC) gene plus the acquisition of a somatic mutation, leading to complete inactivation of the APC tumor suppressor gene.4 Familial adenomatosis polyposis should be excluded by colonoscopy if FGPs are numerous, large (>1 cm), or dysplasic.3 For sporadic FGPs, up to 23% are associated with proton pump inhibitor (PPI) use.5, 6 A recent review with meta-analysis indicated that long-term use of PPIs (≥12 months) increased the risk of FGPs (pooled odds ratio [confidence interval]: 3.81 [2.78-5.24] for the fixed effects model and 2.88 [0.97-8.55] for the random effects model).7 The risk was even higher if the exposure duration was more than 48 months (pooled odds ratio: 4.02). There is no or inverse association with Helicobacter pylori infection.1, 3 FGPs rarely harbor dysplastic lesions. A study in the USA of 35 372 FGPs found that only 0.3% had low-grade dysplasia.5 Moreover, even syndromic FGPs rarely progress to cancer.8 Once epithelial gastric polyps are found at initial endoscopy, it is important to sample polyps and/or normal-appearing gastric mucosa to establish histological diagnosis and to define who needs surveillance. Biopsies from the background antrum and corpus mucosa could rule out atrophic gastritis, intestinal metaplasia, dysplasia, and H. pylori infection. All these information is important for the management of other epithelial gastric polyps, including hyperplastic polyp, adenoma, and type 1 or 2 gastric neuroendocrine tumors.3 Once sporadic FGPs are diagnosed, routine endoscopic surveillance is not recommended in the absence of dysplasia. There is still no consensus on the indication of endoscopy resection of sporadic FGPs. However, many experts suggest the removal of FGPs larger than 10 mm.3 Few studies have considered risk factors other than age, gender, PPIs, and H. pylori infection for sporadic FGPs. A recent one-center, endoscopy-based retrospective study in Taiwan indicated the incidence of FGPs increased from 0.6% in 2010 to 1.3% in 2015.9 The controls were age- and gender-matched subjects who received upper endoscopy during the similar period with the cases. The authors found the presence of liver cirrhosis, gastric ulcer, duodenal ulcer (adjusted odds ratio: 0.18, 0.28, and 0.35, respectively, all P < 0.001), but not reflux esophagitis, were inversely associated with FGP risk. FGPs are commonly seen in patients with relatively healthy gastric mucosa. This is an interesting finding that implies causative factors to gastric mucosa, including cirrhosis and peptic ulcers, which could reduce the formation of FGPs, probably through the facilitation of glandular outflow. However, more than 30% of H. pylori status was missing, and the information of PPI exposure was less than adequate in this study. Future studies are necessary to support this finding and the proposed mechanism behind it. The author declares no conflict of interest.

POSTTRAUMMATIC HISTOGENESIS OF THE PERITONEAL MESOTHELIUM UNDER CONDITIONS OF REPARATIVE REGENERATION FOR ADHESIVE DISEASE

A quantitative assessment of the tissue organization of the parietal peritoneal mesothelium under conditions of influencing the vegetative centers of vascular regulation during reparative regeneration was carried out in the study. The results indicate that stimulation of sympathetic innervation is accompanied by a decrease in mitotic activity due to disorders of microcirculation, transcapillary exchange, and drainage processes in the peritoneal tissues. Along with the distortion of the process of collagenogenesis, this causes a hyperplastic type of regeneration.

Epithelial Deletion of Sulf2 Exacerbates Bleomycin-Induced Lung Injury, Inflammation, and Mortality.

Epithelial injury has been proposed to be the initiating factor in the pathogenesis of idiopathic pulmonary fibrosis (IPF). We have shown previously that heparan sulfate 6-O-endosulfatase (Sulf) 2 is overexpressed in the hyperplastic type II alveolar epithelial cells (AECs) in the IPF lungs. By removing 6-O-sulfates from specific heparan sulfate intrachain sites, Sulf2 modulates the functions of many growth factors and cytokines. In this study, we hypothesized that Sulf2 plays a regulatory role in alveolar epithelial injury and repair, using the murine bleomycin model. Consistent with our findings in human IPF lungs, bleomycin treatment in mice resulted in up-regulation of Sulf2 mRNA in whole-lung extracts and overexpression of Sulf2 protein in type II AECs on lung tissue sections. Sulf2 protein was detectable in bronchoalveolar lavage fluid at baseline, and its level was significantly increased after bleomycin exposure. To study the role of Sulf2 in alveolar injury and repair in vivo, we generated a doxycycline-inducible epithelial-specific Sulf2 conditional knockout (Sulf2 CKO) mouse line. After bleomycin exposure, Sulf2 CKO mice exhibited enhanced neutrophil infiltration in the lung, with elevated levels of total protein, lactate dehydrogenase, and cytokines (granulocyte colony-stimulating factor and interferon-γ-inducible protein 10) in bronchoalveolar lavage fluid compared with wild-type littermates. We further showed that both the p53-p21 DNA damage response and the transforming growth factor-β1 signaling pathway were up-regulated in Sulf2 CKO mice compared with wild-type. Finally, Sulf2 CKO mice suffered increased mortality after bleomycin exposure. In conclusion, Sulf2 expression in type II AECs plays a protective role in epithelial injury, inflammation and mortality.

Cobalt nanoparticles induce lung injury, DNA damage and mutations in mice

BackgroundWe and other groups have demonstrated that exposure to cobalt nanoparticles (Nano-Co) caused oxidative stress and inflammation, which have been shown to be strongly associated with genotoxic and carcinogenic effects. However, few studies have reported Nano-Co-induced genotoxic effects in vivo. Here, we propose that Nano-Co may have high genotoxic effects due to their small size and high surface area, which have high capacity for causing oxidative stress and inflammation.Methodsgpt delta transgenic mice were used as our in vivo study model. They were intratracheally instilled with 50 μg per mouse of Nano-Co. At day 1, 3, 7 and 28 after exposure, bronchoalveolar lavage (BAL) was performed and the number of neutrophils, CXCL1/KC level, LDH activity and concentration of total protein in the BAL fluid (BALF) were determined. Mouse lung tissues were collected for H&E staining, and Ki-67, PCNA and γ-H2AX immunohistochemical staining. 8-OHdG level in the genomic DNA of mouse lungs was determined by an OxiSelect™ Oxidative DNA Damage ELISA Kit, and mutant frequency and mutation spectrum in the gpt gene were also determined in mouse lungs at four months after Nano-Co exposure by 6-TG selection, colony PCR, and DNA sequencing.ResultsExposure of mice to Nano-Co (50 μg per mouse) resulted in extensive acute lung inflammation and lung injury which were reflected by increased number of neutrophils, CXCL1/KC level, LDH activity and concentration of total protein in the BALF, and infiltration of large amount of neutrophils and macrophages in the alveolar space and interstitial tissues. Increased immunostaining of cell proliferation markers, Ki-67 and PCNA, and the DNA damage marker, γ-H2AX, was also observed in bronchiolar epithelial cells and hyperplastic type II pneumocytes in mouse lungs at day 7 after Nano-Co exposure. At four months after exposure, extensive interstitial fibrosis and proliferation of interstitial cells with inflammatory cells infiltrating the alveolar septa were observed. Moreover, Nano-Co caused increased level of 8-OHdG in genomic DNA of mouse lung tissues. Nano-Co also induced a much higher mutant frequency as compared to controls, and the most common mutation was G:C to T:A transversion, which may be explained by Nano-Co-induced increased formation of 8-OHdG.ConclusionOur study demonstrated that exposure to Nano-Co caused oxidative stress, lung inflammation and injury, and cell proliferation, which further resulted in DNA damage and DNA mutation. These findings have important implications for understanding the potential health effects of nanoparticle exposure.