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1.
Medicine (Baltimore) ; 99(43): e22351, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33120736

RESUMO

Asthma is a chronic inflammatory and multifactorial respiratory tract disease. It affects over 18 million adults and 6 million children in the USA with Puerto Ricans showing the highest prevalence (12%-19%). This airways illness can be triggered by an environmental stimulus such as grass pollen, fungi spores, cockroaches allergens, dust mites metabolic compounds, and importantly, by environmental proteases such as trypsin and tryptase. Because of the pivotal role of proteases in the onset of asthma pathophysiology, we focused this study on the serine Protease Activated Receptor-2 (PAR-2), a G-protein-coupled receptor widely expressed in cells across the respiratory tract. Herein, we measured the activation of PAR-2 on primary pulmonary bronchial/tracheal epithelial cells, human small airway epithelial cells, lung bronchial smooth muscle cells (with and without asthma). We tested human-derived eosinophils from 61 Puerto Rican participants (33 asthmatic and 28 non-asthmatic). As surrogate of PAR-2 activation or inhibition we used intracellular calcium mobilization assay. We hypothesized that following exposure of the PAR-2 agonist (AC264613), the studied human primary cell types will increase the mobilization of intracellular calcium levels. In contrast, we expected a decrease of the intracellular calcium levels upon exposure to a PAR-2 antagonist (FSLLRY-NH2). The Puerto Rican-derived eosinophils were analyzed for the proinflammatory markers MAPK/PI3K using flow cytometry (n = 8). As expected, the PAR-2 agonist significantly increased the activation of PAR-2 on the bronchial/tracheal epithelial cells, bronchial smooth muscle cells and human small airway epithelial cells (P = .01). The PAR-2 antagonist significantly decreased the intracellular calcium levels of these lung primary down to undetectable levels (P = .01). Remarkably, the asthmatic-derived eosinophils showed a striking 300% increase of intracellular calcium mobilization suggesting a severe response to the PAR-2 agonist stimuli in asthmatics. In contrast, there were no significant changes between groups after adding the PAR-2 antagonist. Our outcomes revealed that PAR-2 antagonist effectively inhibited the studied primary cells, expecting to decrease the immune response of eosinophils. Most importantly, our results reveal a promising role for the PAR-2 antagonist in targeting bronchial/tracheal epithelial cells, human small airway epithelial cells and bronchial smooth muscle cells with the potential to oblige an asthma adjuvant therapy.


Assuntos
Asma/tratamento farmacológico , Receptor PAR-2/antagonistas & inibidores , Asma/metabolismo , Biomarcadores/metabolismo , Brônquios/patologia , Cálcio/metabolismo , Sinalização do Cálcio , Células Cultivadas , Eosinófilos/efeitos dos fármacos , Eosinófilos/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Citometria de Fluxo , Humanos , Pulmão/patologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Músculo Liso/patologia , Fosfatidilinositol 3-Quinase/metabolismo , Receptor PAR-2/agonistas , Receptor PAR-2/metabolismo , Transdução de Sinais , Traqueia/patologia
2.
Niger J Clin Pract ; 23(9): 1215-1220, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32913159

RESUMO

Background: Benign Prostatic Hypertrophy [BPH] is associated with voiding dysfunctions. Urodynamic study is the gold standard for diagnosis of voiding dysfunctions but is invasive. Bladder wall thickness (BWT), post-void urine residue (PVR), and bladder emptying efficiency (BEE) are noninvasive predictors of voiding dysfunction. Objective: To study the relationship among BWT, PVR, and BEE in BPH. Subjects and Methods: A hospital-based cross-sectional prospective study of new BPH patients at Nnamdi Azikiwe University Teaching Hospital, Nnewi. The participants had abdominal ultrasonography measurement of anterior BWT (at bladder volume ≥200 mls), prostate volume (PV), and PVR using Prosound SSD3500 (Aloka Co Ltd, Tokyo, Japan) with an abdominal probe frequency of 3.5 MHz. Then the BEE was calculated. The anterior BWT was divided into two groups: <5 mm and ≥5 mm. The data were analyzed using SPSS version 20. Pearson's correlation was used to assess correlation and the differences between the means of the two groups of BWT were compared by Mann-Whitney test. A P- Value <0.05 was considered significant. Results: Seventy seven men with a mean age of 66.66 ± 10.74 years were included in the study. Sixty one percent had symptoms lasting >12 months. The average anterior BWT, PBV, PVR, BEE, PV, and PSA were 4.55 ± 1.02 mm, 260.98 ± 57.44 mls, 58.36 ± 52.94 mls, 77.98 ± 17.37%, 66.31 ± 46.38 mls, and 8.04 ± 5.97 ng/ml, respectively. There was a significant positive correlation between BWT and duration of symptoms (P = 0.044) and a significant negative correlation between BWT and BEE (P = 0.005). An insignificant positive correlation was found between BWT and PVR (P = 0.255). Fifty four (70.1%) had BWT <5 mm and 29.9% had BWT ≥5 mm. The mean IPSS (P = 0.000), PV (P = 0.032) and PVR (P = 0.020) were significantly higher in the ≥5 mm group. The ≥5 mm group also had a significantly lower BEE (P = 0.002). Conclusion: Voiding dysfunction was more severe in patients with BWT of 5 mm or more. There was a positive, but insignificant, correlation between anterior BWT and PVR and a significant negative correlation between BWT and BEE.


Assuntos
Hiperplasia Prostática/patologia , Ultrassonografia/métodos , Bexiga Urinária/diagnóstico por imagem , Retenção Urinária , Transtornos Urinários/patologia , Idoso , Estudos Transversais , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Liso/anatomia & histologia , Músculo Liso/diagnóstico por imagem , Músculo Liso/patologia , Nigéria , Estudos Prospectivos , Hiperplasia Prostática/complicações , Bexiga Urinária/anatomia & histologia , Bexiga Urinária/fisiopatologia , Transtornos Urinários/diagnóstico por imagem , Transtornos Urinários/etiologia , Urodinâmica
3.
Nat Commun ; 11(1): 4328, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32859919

RESUMO

The general anesthetic ketamine has been repurposed by physicians as an anti-depressant and by the public as a recreational drug. However, ketamine use can cause extensive pathological changes, including ketamine cystitis. The mechanisms of ketamine's anti-depressant and adverse effects remain poorly understood. Here we present evidence that ketamine is an effective L-type Ca2+ channel (Cav1.2) antagonist that directly inhibits calcium influx and smooth muscle contractility, leading to voiding dysfunction. Ketamine prevents Cav1.2-mediated induction of immediate early genes and transcription factors, and inactivation of Cav1.2 in smooth muscle mimics the ketamine cystitis phenotype. Our results demonstrate that ketamine inhibition of Cav1.2 signaling is an important pathway mediating ketamine cystitis. In contrast, Cav1.2 agonist Bay k8644 abrogates ketamine-induced smooth muscle dysfunction. Indeed, Cav1.2 activation by Bay k8644 decreases voiding frequency while increasing void volume, indicating Cav1.2 agonists might be effective drugs for treatment of bladder dysfunction.


Assuntos
Ketamina/efeitos adversos , Transdução de Sinais/efeitos dos fármacos , Animais , Cálcio/metabolismo , Canais de Cálcio Tipo L/efeitos dos fármacos , Canais de Cálcio Tipo L/genética , Proliferação de Células , Cistite/induzido quimicamente , Modelos Animais de Doenças , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Camundongos , Camundongos Knockout , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Músculo Liso/patologia , Oócitos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Bexiga Urinária/patologia , Xenopus
4.
J Cancer Res Ther ; 16(3): 647-652, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32719283

RESUMO

The leiomyoma is a benign smooth-muscle neoplasm commonly found in the female genital tract, gastrointestinal tract, or skin. Leiomyomas of the oral cavity are unusual. Oral leiomyomas are uncommon due to the paucity of the smooth muscle in the mouth (except in blood vessels) and thus the involvement of jaw bones is extremely rare. Leiomyomas have been classified as solid angiomyoma, angioleiomyoma (vascular leiomyoma), and epithelioid variants. Angioleiomyomas are benign mesenchymal tumors derived from smooth muscle, which rarely occur in the oral cavity. Malignant transformation probably does not occur but careful histopathologic examination is still necessary to differentiate these benign lesions from their malignant counterparts due to different prognosis. Although uncommon in the maxilla and mandible, they should be included in the differential diagnosis of radiolucent lesions of jaw bones. An extensive search of literature was carried out on the Medline-PubMed and Google Scholar database using the keywords such as leiomyoma, angioleiomyoma, jaw bones, maxilla, mandible, intra-osseous to thoroughly search and collect all the reported cases of intraosseous leiomyoma (but our search was not limited to these terms only). To the best of our knowledge, only 23 cases of intraosseous leiomyomas have been reported so far in the jaw bones, among which only 8 belonged to angioleiomyomas. Herein, we report the 9th case of intraosseous angioleiomyoma, one of the variants of leiomyoma and overall 24th intraosseous leiomyoma in a 6-year-old female child, together with conventional histopathologic and immunohistochemical findings.


Assuntos
Angiomioma/patologia , Neoplasias Mandibulares/patologia , Doenças Raras/patologia , Actinas/metabolismo , Angiomioma/metabolismo , Angiomioma/cirurgia , Antígenos CD34/metabolismo , Biomarcadores Tumorais/metabolismo , Criança , Feminino , Humanos , Neoplasias Mandibulares/metabolismo , Neoplasias Mandibulares/cirurgia , Músculo Liso/metabolismo , Músculo Liso/patologia , Doenças Raras/metabolismo , Doenças Raras/cirurgia
5.
PLoS Pathog ; 16(7): e1008651, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32658914

RESUMO

Type-2 immunity elicits tissue repair and homeostasis, however dysregulated type-2 responses cause aberrant tissue remodelling, as observed in asthma. Severe respiratory viral infections in infancy predispose to later asthma, however, the processes that mediate tissue damage-induced type-2 inflammation and the origins of airway remodelling remain ill-defined. Here, using a preclinical mouse model of viral bronchiolitis, we find that increased epithelial and mesenchymal high-mobility group box 1 (HMGB1) expression is associated with increased numbers of IL-13-producing type-2 innate lymphoid cell (ILC2s) and the expansion of the airway smooth muscle (ASM) layer. Anti-HMGB1 ablated lung ILC2 numbers and ASM growth in vivo, and inhibited ILC2-mediated ASM cell proliferation in a co-culture model. Furthermore, we identified that HMGB1/RAGE (receptor for advanced glycation endproducts) signalling mediates an ILC2-intrinsic IL-13 auto-amplification loop. In summary, therapeutic targeting of the HMGB1/RAGE signalling axis may act as a novel asthma preventative by dampening ILC2-mediated type-2 inflammation and associated ASM remodelling.


Assuntos
Remodelação das Vias Aéreas/imunologia , Proteína HMGB1/imunologia , Inflamação/imunologia , Linfócitos/imunologia , Músculo Liso/imunologia , Animais , Camundongos , Músculo Liso/patologia , Receptor para Produtos Finais de Glicação Avançada/imunologia
6.
Am J Pathol ; 190(9): 1843-1858, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32479820

RESUMO

The progression of Crohn disease to intestinal stricture formation is poorly controlled, and the pathogenesis is unclear, although increased smooth muscle mass is present. A previously described rat model of trinitrobenzenesulfonic acid-induced colitis is re-examined here. Although inflammation of the mid-descending colon typically resolved, a subset showed characteristic stricturing by day 16, with an inflammatory infiltrate in the neuromuscular layers including eosinophils, CD3-positive T cells, and CD68-positive macrophages. Closer study identified CD163-positive, CD206-positive, and arginase-positive cells, indicating a M2 macrophage phenotype. Stricturing involved ongoing proliferation of intestinal smooth muscle cells (ISMC) with expression of platelet-derived growth factor receptor beta and progressive loss of phenotypic markers, and stable expression of hypoxia inducible factor 1 subunit alpha. In parallel, collagen I and III showed a selective and progressive increase over time. A culture model of the stricture phenotype of ISMC showed stable hypoxia inducible factor 1 subunit alpha expression that promoted growth and improved both survival and growth in models of experimental ischemia. This phenotype was hyperproliferative to serum and platelet-derived growth factor BB, and unresponsive to transforming growth factor beta, a prominent cytokine of M2 macrophages, compared with control ISMC. We identified a hyperplastic phenotype of ISMC, uniquely adapted to an ischemic environment to drive smooth muscle layer expansion, which may reveal new targets for treating intestinal fibrosis.


Assuntos
Doença de Crohn/patologia , Intestinos/patologia , Macrófagos/metabolismo , Músculo Liso/patologia , Animais , Constrição Patológica/induzido quimicamente , Constrição Patológica/patologia , Hiperplasia/induzido quimicamente , Hiperplasia/metabolismo , Hiperplasia/patologia , Músculo Liso/metabolismo , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Fenótipo , Ratos , Ratos Sprague-Dawley , Ácido Trinitrobenzenossulfônico/toxicidade
7.
J Neuropathol Exp Neurol ; 79(7): 719-733, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32529201

RESUMO

Competence in muscle biopsy evaluation is a core component of neuropathology practice. The practicing neuropathologist should be able to prepare frozen sections of muscle biopsies with minimal artifacts and identify key histopathologic features of neuromuscular disease in hematoxylin and eosin-stained sections as well as implement and interpret a basic panel of additional histochemical, enzyme histochemical, and immunohistochemical stains. Important to everyday practice is a working knowledge of normal muscle histology at different ages, muscle motor units, pitfalls of myotendinous junctions, nonpathologic variations encountered at traditional and nontraditional muscle sites, the pathophysiology of myonecrosis and regeneration, and approaches to distinguish muscular dystrophies from inflammatory myopathies and other necrotizing myopathies. Here, we provide a brief overview of what every neuropathologist needs to know concerning the muscle biopsy.


Assuntos
Músculo Esquelético/patologia , Músculo Liso/patologia , Doenças Neuromusculares/patologia , Neuropatologia/normas , Biópsia/métodos , Biópsia/normas , Humanos , Neuropatologia/educação , Neuropatologia/métodos
9.
Arch Biochem Biophys ; 688: 108403, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32418893

RESUMO

Myopia is a main cause of preventable or treatable visual impairment, it has become a major public health issue due to its increasingly high prevalence worldwide. Currently, it is confirmed that the development of myopia is associated with the disorders of accommodation. As a dominant factor for accommodation, ciliary muscle contraction/relaxation can regulate the physiological state of the lens and play a crucial role in the development of myopia. To investigate the relationship between myopia and ciliary muscle, the guinea pigs were randomly divided into a normal control (NC) group and a negative lens-induced myopia (LIM) group, and the animals in each group were further randomly assigned into 2-week (n = 18) and 4-week (n = 21) subgroups in accordance with the duration of myopic induction of 2 and 4 weeks, respectively. In the present study, right eyes of the animals in LIM group were covered with -6.0 D lenses to induce myopia. Next, we performed the haematoxylin and eosin (H&E) staining to observe the pathological change of ciliary muscle, determined the contents of adenosine triphosphate (ATP) and lactate acid (LA), and measured the Na+/K+-ATPase expression and activity in ciliary muscles in both NC and LIM groups. Moreover, we also analyzed the potassium ion (K+) flux in ciliary muscles from 4-week NC and LIM guinea pigs. As a result, we found that the arrangements of ciliary muscles in LIM guinea pigs were broken, dissolved or disorganized; the content of ATP decreased, whereas the content of LA increased in ciliary muscles from LIM guinea pigs. Monitoring of K+ flux in ciliary muscles from LIM guinea pigs demonstrated myopia-triggered K+ influx. Moreover, we also noted a decreased expression of Na+/K+-ATPase (Atp1a1) at both mRNA and protein levels and reduced activity in ciliary muscles from LIM guinea pigs. Overall, our results will facilitate the understanding of the mechanism associated with inhibitory Na+/K+-ATPase in lens-induced myopia and which consequently lead to the disorder of microenvironment within ciliary muscles from LIM guinea pigs, paving the way for a promising adjuvant approach in treating myopia in clinical practice.


Assuntos
Olho/metabolismo , Homeostase/fisiologia , Músculo Liso/metabolismo , Miopia/metabolismo , Potássio/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Olho/patologia , Cobaias , Ácido Láctico/metabolismo , Masculino , Músculo Liso/patologia , Miopia/patologia , RNA Mensageiro/metabolismo , ATPase Trocadora de Sódio-Potássio/genética , ATPase Trocadora de Sódio-Potássio/metabolismo
10.
Sci Rep ; 10(1): 6754, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32317758

RESUMO

Asthma is a heterogeneous disease characterized by chronic inflammation and structural changes in the airways. The airway smooth muscle (ASM) is responsible for airway narrowing and an important source of inflammatory mediators. We and others have previously shown that WNT5A mRNA and protein expression is higher in the ASM of asthmatics compared to healthy controls. Here, we aimed to characterize the functional role of (smooth muscle-derived) WNT5A in asthma. We generated a tet-ON smooth-muscle-specific WNT5A transgenic mouse model, enabling in vivo characterization of smooth-muscle-derived WNT5A in response to ovalbumin. Smooth muscle specific WNT5A overexpression showed a clear trend towards enhanced actin (α-SMA) expression in the ASM in ovalbumin challenged animals, but had no effect on collagen content. WNT5A overexpression in ASM also significantly enhanced the production of the Th2-cytokines IL4 and IL5 in lung tissue after ovalbumin exposure. In line with this, WNT5A increased mucus production, and enhanced eosinophilic infiltration and serum IgE production in ovalbumin-treated animals. In addition, CD4+ T cells of asthma patients and healthy controls were stimulated with WNT5A and changes in gene transcription assessed by RNA-seq. WNT5A promoted expression of 234 genes in human CD4+ T cells, among which the Th2 cytokine IL31 was among the top 5 upregulated genes. IL31 was also upregulated in response to smooth muscle-specific WNT5A overexpression in the mouse. In conclusion, smooth-muscle derived WNT5A augments Th2 type inflammation and remodelling. Our findings imply a pro-inflammatory role for smooth muscle-derived WNT5A in asthma, resulting in increased airway wall inflammation and remodelling.


Assuntos
Remodelação das Vias Aéreas/imunologia , Asma/imunologia , Linfócitos T CD4-Positivos/imunologia , Pulmão/imunologia , Músculo Liso/imunologia , Proteína Wnt-5a/imunologia , Actinas/genética , Actinas/imunologia , Remodelação das Vias Aéreas/genética , Alérgenos/administração & dosagem , Animais , Asma/induzido quimicamente , Asma/genética , Asma/patologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/patologia , Movimento Celular , Eosinófilos/imunologia , Eosinófilos/patologia , Feminino , Regulação da Expressão Gênica , Humanos , Imunoglobulina E/biossíntese , Interleucina-4/genética , Interleucina-4/imunologia , Interleucina-5/genética , Interleucina-5/imunologia , Interleucinas/genética , Interleucinas/imunologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Músculo Liso/química , Músculo Liso/patologia , Ovalbumina/administração & dosagem , Cultura Primária de Células , Transgenes , Proteína Wnt-5a/genética , Proteína Wnt-5a/farmacologia
11.
Am J Clin Pathol ; 154(2): 208-214, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32253420

RESUMO

OBJECTIVES: Bladder cancers invading the muscularis mucosae (MM) are treated differently from those invading the muscularis propria (MP). However, it may be difficult to determine the type of smooth muscle in transurethral resection (TUR) or biopsy specimens. We aimed to investigate the clinicopathologic features of bladder cancers involving smooth muscle of indeterminate type (SMIT) in TUR specimens in comparison with those invading the MM. METHODS: We identified 103 patients with bladder cancer involving SMIT (n = 27) or the MM (n = 76) in TUR specimens. All patients underwent subsequent restaging TUR or cystectomy. RESULTS: Bladder cancer with SMIT invasion showed a significantly higher rate of MP invasion in the subsequent specimens than those invading the MM (52% vs 29%). Lack of MP in the TUR specimens had a significantly higher risk of MP invasion in the subsequent specimens than those with the MP (61% vs 40%). The overall survival time for patients with SMIT invasion was significantly shorter than those with MM invasion. CONCLUSIONS: Bladder cancers with SMIT invasion in TUR specimens show more frequent cancer upstaging in the subsequent specimens and a poorer clinical outcome than those invading the MM, which highlights the importance of a cancer restaging procedure for these patients.


Assuntos
Carcinoma de Células de Transição/patologia , Membrana Mucosa/patologia , Músculo Liso/patologia , Invasividade Neoplásica/patologia , Neoplasias da Bexiga Urinária/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Carcinoma de Células de Transição/cirurgia , Cistectomia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Membrana Mucosa/cirurgia , Músculo Liso/cirurgia , Resultado do Tratamento , Bexiga Urinária/patologia , Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/cirurgia , Urotélio/patologia , Urotélio/cirurgia
12.
Hum Pathol ; 99: 27-35, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32220606

RESUMO

Smooth muscle hyperplasia of the testicular adnexa (SMH-TA) is a rare mass-forming intrascrotal lesion. Although benign, it can be a diagnostic challenge, as we have seen in our consult practice. Herein, we discuss our experience with these lesions over 14 years. Twelve SMH-TA cases were identified in our institutional records between 2005 and 2019. The morphologic features were reviewed. Clinical information was obtained from physicians' notes. The mean age was 51 years (range, 24-82 years). Six cases were on the left side, five on the right, and one was bilateral. The most common presentations were orchialgia (n = 10) and mass (n = 6). Two patients had a concurrent incarcerated inguinal hernia, and one had a recent groin trauma. Past medical history included 5 patients with previous surgeries in the inguinal region, 2 with a history of treated infections, and 1 with persistent chronic orchitis. Eight patients have undergone ultrasound imaging which showed lesions (n = 4), hematoma (n = 1), undescended testis (n = 1), or no abnormalities (n = 2). Grossly, the mean size was 1.7 cm (range, 1.0-3 cm). The lesions had ill-defined, focally cystic, pink-tan nodular surface. Microscopically, the lesions were comprised of an ill-defined smooth muscle proliferation arranged in fascicles or haphazard fashion, growing in a periductal, perivascular, interstitial, or most commonly in a mixed pattern. SMH-TA is a rare benign entity that can present clinically as orchialgia and/or a suspicious intrascrotal mass. As suggested in previous studies, we believe that this lesion represents a reactive process.


Assuntos
Proliferação de Células , Músculo Liso/patologia , Miócitos de Músculo Liso/patologia , Doenças Testiculares/patologia , Testículo/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Bases de Dados Factuais , Diagnóstico Diferencial , Humanos , Hiperplasia , Masculino , Pessoa de Meia-Idade , Músculo Liso/cirurgia , Valor Preditivo dos Testes , Doenças Testiculares/cirurgia , Testículo/cirurgia , Adulto Jovem
13.
Am J Clin Pathol ; 153(6): 760-771, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32010932

RESUMO

OBJECTIVES: Histopathologic characteristics of choledochal cysts and their clinical implications have not been previously comprehensively studied. METHODS: Smooth muscle distribution patterns and other histologic findings (inflammation, metaplasia, dysplasia, and heterotopia) in 233 surgically resected choledochal cysts were evaluated. RESULTS: Mean patient age was 23.3 ±â€…19.8 years, with male:female ratio of 0.3. Most cases were Todani type I (175 cases, 75.1%) or IVa (56 cases, 24.1%). Choledochal cysts with thin scattered/no muscle fiber (175 cases, 75.1%) were the predominant pattern and were associated with more frequent postoperative biliary stricture (P = .031), less frequent pyloric metaplasia (P = .016), and mucosal smooth muscle aggregates (P < .001) compared to cysts with thick muscle bundles. Severe chronic cholangitis (P = .049), pyloric metaplasia (P = .019), mucosal smooth muscle aggregates (P < .001), biliary intraepithelial neoplasia (P = .021), and associated bile duct (P = .021) and gallbladder carcinomas (P = .03) were more common in adults (age >20 years vs ≤20 years), suggesting that chronic irritation in association with developmental anomalies involves tumorigenesis from choledochal cysts. CONCLUSION: Smooth muscle distribution pattern of choledochal cyst may predict postoperative complication, raising clinical implications of smooth muscle patterns in postoperative management of choledochal cysts.


Assuntos
Cisto do Colédoco/patologia , Músculo Liso/patologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Cisto do Colédoco/cirurgia , Feminino , Humanos , Hiperplasia/patologia , Lactente , Recém-Nascido , Inflamação/patologia , Masculino , Metaplasia/patologia , Pessoa de Meia-Idade , Adulto Jovem
15.
Am J Physiol Lung Cell Mol Physiol ; 318(5): L900-L907, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32101015

RESUMO

The hyperconstriction of airway smooth muscle (ASM) is the main driving mechanism during an asthmatic attack. The airway lumen is reduced, resistance to airflow increases, and normal breathing becomes more difficult. The tissue contraction can be temporarily relieved by using bronchodilator drugs, which induce relaxation of the constricted airways. In vitro studies indicate that relaxation of isolated, precontracted ASM is induced by mechanical oscillations in healthy subjects but not in asthmatic subjects. Further, short-term acute asthmatic subjects respond to superimposed pressure oscillations (SIPO) generated in the range of 5-15 Hz with ~50% relaxation of preconstricted sensitized airways. Mechanical oscillations, and specifically SIPO, are not widely characterized in asthmatic models. The objective of this in vivo study is to determine the effects of a range of oscillation patterns similar to our previous acute study differing from normal breathing. Both healthy and sensitized mice were observed, with their responses to SIPO treatments measured during induced bronchoconstriction resulting from acetylcholine (Ach) challenge. SIPO-generated results were compared with data from treatments using the bronchorelaxant isoproterenol (ISO). The study shows that SIPO in the range of 5-20 Hz induces relaxation in chronic sensitized airways, with significant improvements in respiratory parameters at SIPO values near 1.7 cmH2O irrespective of the frequency of generation.


Assuntos
Asma/terapia , Pulmão/imunologia , Músculo Liso/imunologia , Acetilcolina/farmacologia , Alérgenos/administração & dosagem , Animais , Antígenos de Plantas/administração & dosagem , Aspergillus/química , Aspergillus/imunologia , Asma/induzido quimicamente , Asma/imunologia , Asma/patologia , Fenômenos Biomecânicos/imunologia , Broncoconstrição/efeitos dos fármacos , Broncodilatadores/farmacologia , Modelos Animais de Doenças , Feminino , Fungos/química , Fungos/imunologia , Isoproterenol/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/patologia , Extratos Vegetais/administração & dosagem , Pressão , Pyroglyphidae/química , Pyroglyphidae/imunologia , Testes de Função Respiratória
16.
Am J Surg Pathol ; 44(6): 834-837, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31985498

RESUMO

Brown bowel syndrome (BBS) is a rare condition associated with vitamin E deficiency and defined by prominent lipofuscin deposition in the muscularis propria. Eight unique cases of BBS were identified: 5 men and 3 women (mean age=58.6 y). Pertinent comorbidities included bariatric surgery=2, malnourishment=2, Crohn=2, cystic fibrosis=1, alcohol and cocaine abuse=1, and prior small bowel resections=1. Presenting symptoms included abdominal pain=3, bleeding=1, nausea and vomiting=1, and nonresponsiveness=1. Imaging studies were often abnormal: thickened bowel wall=3 (1 with a mass), small bowel obstruction=2, and edematous and dilated bowel wall=2. Most specimens were surgical resections (n=7, autopsy=1): extended right colectomy=2, small bowel only=5 (terminal ileum=3, jejunum=2). Two specimens were grossly described as mahogany, and 1 case contained a perforation. Histologic sections of all cases showed finely granular, brown cytoplasmic pigment in smooth muscle cells on hematoxylin and eosin. This pigment was most conspicuous in the muscularis propria (small bowel>colon), and it was not identified in the mucosa. The pigment was reactive with Fontana-Masson, carbol lipofuscin, Periodic acid-Schiff, and Periodic acid-Schiff with diastase, and electron microscopy was compatible with lipofuscin. The mean clinical follow-up was 208 weeks: 1 patient died of complications of encephalitis, the others were alive and well. BBS is important to recognize because it is linked with malnutrition, specifically vitamin E deficiency, and it can (rarely) clinically simulate malignancy. The diagnosis is based on the identification of the lipofuscin pigment in the cytoplasm of smooth muscle cells, which is most easily seen in the muscularis propria of the small bowel.


Assuntos
Colo/patologia , Enteropatias/patologia , Lipofuscina , Músculo Liso/patologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome
17.
Am J Physiol Renal Physiol ; 318(3): F549-F556, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31904287

RESUMO

Partial bladder outlet obstruction (pBOO) results in bladder fibrosis that is initiated by an inflammatory cascade and the decompensation after smooth muscle hypertrophy. We have been using an animal model to develop the hypothesis that mesenchymal stem cells (MSCs) are able to mitigate this cytokine cascade and prevent bladder deterioration. We hypothesized that intraperitoneal administration of MSCs can produce the same effects as intravenously administered cells but may require higher dosing. Intraperitoneal treatment will provide insights into the mechanisms of action and may offer advantages over intravenous administration, as it will permit allow higher doses and potentially reduce systemic exposure. Rats underwent a surgical induction of pBOO and instillation of either 1 × 106 or 5 × 106 commercially acquired MSCs into the peritoneum. RT-PCR, immunohistochemistry, and urodynamics were used to compare treatment groups with controls. pBOO resulted in a marked, statistically significant, upregulation of inflammatory markers in the bladder, including transforming growth factor-ß, hypoxia-inducible factor-1α, hypoxia-inducible factor-3α, mammalian target of rapamycin, and collagen types I and III. Moderate but inconsistent levels of downregulation were seen with 1 × 106 MSCs, but excellent and reliable downregulation was seen with 5 × 106 MSCs (P < 0.05). Immunohistochemistry confirmed that protein levels were affected in accordance with mRNA upregulation. Urodynamics demonstrated MSC treatment resulted in whole organ physiological benefits, as they prevented elevations in detrusor pressure. In conclusion, intraperitoneal administration of MSCs resulted in a similar effect as intravenous administration; however, this required a higher dose. This has significant implications for determining the mechanism of action and potential clinical application for human therapy.


Assuntos
Transplante de Células-Tronco Mesenquimais/métodos , Obstrução do Colo da Bexiga Urinária/terapia , Animais , Feminino , Fibrose/patologia , Regulação da Expressão Gênica/fisiologia , Hipertrofia/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamação/genética , Inflamação/metabolismo , Injeções Intraperitoneais , Músculo Liso/patologia , Doenças Musculares/patologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Proteína Smad2/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Obstrução do Colo da Bexiga Urinária/patologia , Urodinâmica
18.
Mol Biol Rep ; 47(1): 141-149, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31583569

RESUMO

In the precedent research conducted by the same team, it concluded that the activities in C-type natriuretic peptide (CNP)/cyclic guanosine monophosphate (cGMP)/cyclic adenosine monophosphate (cAMP)/ß-type phospholipase C (PLCß) pathways of rat antral smooth muscle were changed due to diabetes, which was the key pathogenetic mechanism for diabetic gastric dysmotility. As the follow-on step, this study was designed to probe into the downstream signaling pathway of CNP/PLCß. The results showed that level of α-type protein kinase C (PKCα),cell membrane to cytoplasm ratio of PKCα, cell membrane to cytoplasmic ratio of ßI-type protein kinase C (PKCßI) and level of Phosphor-PKCα (P-PKCα) were significantly reduced in diabetes rat antral smooth muscle samples. The content of tetraphosphate inositol (IP4) in gastric antral smooth muscle of diabetic rats reduced, and the content of diacyl-glycerol (DG) was unchanged. CNP significantly decreased the content of IP4 and DG, this effect was more obvious in diabetic rats. Subsequent to the addition of protein kinase A (PKA) blocker N-[2- (p-Bromocin-namylamino)ethyl]-5 -isoquinolinesulfonamide dihydrochloride (H-89) before CNP treatment, the inhibitory effect of CNP was reduced; subsequent to the addition of protein kinase G (PKG) blocker KT5823 before CNP treatment, the inhibitory effect of CNP was also reduced. With the addition of the combination of H-89 and KT5823 before CNP treatment, the inhibition by CNP could be offset. These results were concluded that CNP inhibited the activity of PKC family in rat smooth muscle and reduced the levels of IP4 and DG through the PKG/PKA-PLCß pathways, causing inhibited muscular contractions, which may be a key pathogenetic factor for diabetic gastroparesis.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Diglicerídeos/metabolismo , Gastroparesia/metabolismo , Fosfatos de Inositol/metabolismo , Peptídeo Natriurético Tipo C/farmacologia , Proteína Quinase C/metabolismo , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Motilidade Gastrointestinal/efeitos dos fármacos , Gastroparesia/etiologia , Gastroparesia/patologia , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/patologia , Músculo Liso/fisiologia , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
19.
Am J Respir Cell Mol Biol ; 62(1): 49-60, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31211918

RESUMO

For decades, stem cell therapies for pulmonary hypertension (PH) have progressed from laboratory hypothesis to clinical practice. Promising preclinical investigations have laid both a theoretical and practical foundation for clinical application of mesenchymal stem cells (MSCs) for PH therapy. However, the underlying mechanisms are still poorly understood. We sought to study the effects and mechanisms of MSCs on the treatment of PH. For in vivo experiments, the transplanted GFP+ MSCs were traced at different time points in the lung tissue of a chronic hypoxia-induced PH (CHPH) rat model. The effects of MSCs on PH pathogenesis were evaluated in both CHPH and sugen hypoxia-induced PH models. For in vitro experiments, primary pulmonary microvascular endothelial cells were cultured and treated with the MSC conditioned medium. The specific markers of endothelial-to-mesenchymal transition (EndMT) and cell migration properties were measured. MSCs decreased pulmonary arterial pressure and ameliorated the collagen deposition, and reduced the thickening and muscularization in both CHPH and sugen hypoxia-induced PH rat models. Then, MSCs significantly attenuated the hypoxia-induced EndMT in both the lungs of PH models and primary cultured rat pulmonary microvascular endothelial cells, as reflected by increased mesenchymal cell markers (fibronectin 1 and vimentin) and decreased endothelial cell markers (vascular endothelial cadherin and platelet endothelial cell adhesion molecule-1). Moreover, MSCs also markedly inhibited the protein expression and degradation of hypoxia-inducible factor-2α, which is known to trigger EndMT progression. Our data suggest that MSCs successfully prevent PH by ameliorating pulmonary vascular remodeling, inflammation, and EndMT. Transplantation of MSCs could potentially be a powerful therapeutic approach against PH.


Assuntos
Células Endoteliais/patologia , Transição Epitelial-Mesenquimal/fisiologia , Hipertensão Pulmonar/patologia , Pulmão/metabolismo , Células-Tronco Mesenquimais/patologia , Animais , Diferenciação Celular/fisiologia , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Células Cultivadas , Fibroblastos/patologia , Transplante de Células-Tronco Mesenquimais/métodos , Músculo Liso/patologia , Ratos , Ratos Sprague-Dawley
20.
J Formos Med Assoc ; 119(1 Pt 2): 300-309, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31202500

RESUMO

BACKGROUND/PURPOSE: Pulmonary veno-occlusive disease (PVOD) is a rare but fatal cause of pulmonary hypertension reported to be linked to mutations of eukaryotic initiation factor 2 alpha kinase 4 (EIF2AK4), also known as general control nonderepressible 2 kinase (GCN2). PVOD is difficult to diagnose and often initially misdiagnosed as other types of idiopathic pulmonary arterial hypertension (IPAH). To rapidly and correctly identify PVOD patients and explore the possible pathogenesis, we thoroughly investigated histopathological features and GCN2 protein levels in non-PAH, PVOD and PAH patients. METHODS: Lung specimens were examined for histopathological changes, including those of pulmonary arteries and veins, by Masson's trichrome, modified Verhoeff's and α-SMA staining in the PVOD, IPAH, and non-PAH groups. GCN2 and α-SMA expression in lung tissue was examined by immunohistochemistry and western blotting. RESULTS: PVOD and IPAH patients showed significant intimal and medial thickening of muscular pulmonary arteries compared with non-PAH patients. PVOD patients had more prominent intimal and medial thickening of muscular pulmonary veins than the other two groups. Interestingly, specialized muscle bundles surrounding the tunica adventitia of the pulmonary artery and vein were observed in PVOD patients. A significant decrease in GCN2 expression in the PVOD group was confirmed by immunohistochemistry and western blotting. CONCLUSION: Our study is the first to show remarkable histological structures, including the wreath-like arrangement of a hyperplastic muscle bundle in the adventitia of pulmonary arteries, in PVOD patients as a diagnostic clue and to disclose the biological difference between PAH and PVOD in a Taiwanese population.


Assuntos
Pulmão/patologia , Músculo Liso/patologia , Hipertensão Arterial Pulmonar/patologia , Pneumopatia Veno-Oclusiva/patologia , Actinas/genética , Actinas/fisiologia , Adulto , Idoso , Proliferação de Células , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/fisiologia , Hipertensão Arterial Pulmonar/genética , Artéria Pulmonar/patologia , Veias Pulmonares/patologia , Pneumopatia Veno-Oclusiva/genética , Remodelação Vascular
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