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Background: Continuous local antibiotic perfusion (CLAP) is a method for preserving tissue and function against surgical site infections (SSIs) after shoulder surgery. Methods: To describe the application of the novel CLAP technique to 10 patients with SSIs after shoulder surgery that were not controlled with repeated surgical débridement or elderly patients who are insufficient physical resilience for further surgeries. Results: CLAP, consisting of gentamicin, was performed for 2 weeks, after which the infection was well-controlled. The white blood cell count and C-reactive protein level improved rapidly within 1 week of initiating CLAP, after which the patients were switched to oral antibiotics for 3 months. None of the patients experienced any adverse events. Conclusion: CLAP for SSIs after shoulder surgery was successful in preserving implants and grafts. The SSIs were controlled with no adverse events. CLAP may be an important treatment option for SSIs after shoulder surgery.
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BACKGROUND: Proximal femoral fractures in geriatric patients are a major challenge in orthopedics, often leading to major functional impairment. Early surgical intervention is crucial for improving patient recovery and overall health outcomes. Thus, Japan's Ministry of Health, Labour and Welfare initiated a reimbursement policy in April 2022 to encourage early surgery for these fractures in patients aged ≥75 years. This study investigated the impact of this policy on early surgery rates in Japan and identified factors influencing the timing of surgical interventions. METHODS: We retrospectively analyzed the data of patients who underwent surgery for proximal femoral fractures at our institution between April 2022 and March 2023. Patients were categorized into two groups based on the timing of surgery relative to the injury: ≤48 h and >48 h. Demographic and clinical data, including age, sex, fracture type, and various health- and admission-related factors, were assessed. RESULTS: Of the 192 patients, 152 were included in the study. Among them, 38% underwent early surgery (≤48 h), and 15% of the patients arrived more than 48 h post-injury. Significant differences were found in admission routes and residence types between the groups. The ≤48 h group had shorter intervals from injury to admission and surgery than the >48 h group. Factors such as the admission process, day of the week, and C-reactive protein levels significantly influenced the timing of surgery. CONCLUSIONS: After introducing incentives for early surgery in Japan, 38% of patients with proximal femoral fractures underwent surgery within 48 h of injury. Factors contributing to patients not receiving early surgery included transport from another hospital, weekend hospitalization, and elevated CRP levels. These findings suggest that achieving surgery within 48 h of injury is challenging through hospital efforts alone, and the time criteria might be more appropriate if changed to "admission to surgery."
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Second-generation androgen receptor (AR) signaling inhibitors (ARSIs), such as abiraterone and enzalutamide, prolong the life of patients with castration-resistant prostate cancer (CRPC). However, patients receiving ARSIs ultimately develop resistance through various complex mechanisms, including AR mutations, constitutively active AR-splice variants (AR-Vs), and AR overexpression. Here, we characterized a novel AR pure antagonist, TAS3681, which inhibits AR transcriptional activity and downregulates AR-full length (AR-FL) and AR-Vs. TAS3681 reduced the protein levels of AR-FL and AR-Vs including AR-V7 in enzalutamide-resistant cells (SAS MDV No. 3-14), in vitro and in vivo, showing strong antitumor efficacy in an AR-V7-positive xenograft model. In AR-overexpressing VCaP (prostate cancer) cells, conversely to enzalutamide, TAS3681 effectively suppressed cell proliferation and downregulated AR expression. Importantly, TAS3681 blocked the transcriptional activity of various mutant ARs, including mutations F877L/T878A and H875Y/T878A, which confer resistance to enzalutamide, and V716M and H875Y mutations, which confer resistance to darolutamide. Our results demonstrate that TAS3681 suppresses the reactivation of AR signaling, which causes resistance to ARSIs, via a newly identified mechanism of action. Therefore, TAS3681 could be a new therapeutic option for CRPC treatment.
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Antagonistas de Receptores de Andrógenos , Resistencia a Medicamentos Antineoplásicos , Receptores Androgênicos , Transdução de Sinais , Masculino , Humanos , Receptores Androgênicos/metabolismo , Receptores Androgênicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Antagonistas de Receptores de Andrógenos/farmacologia , Antagonistas de Receptores de Andrógenos/uso terapêutico , Linhagem Celular Tumoral , Animais , Transdução de Sinais/efeitos dos fármacos , Camundongos Nus , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Proliferação de Células/efeitos dos fármacos , Feniltioidantoína/farmacologia , Feniltioidantoína/análogos & derivados , Feniltioidantoína/uso terapêutico , Benzamidas/farmacologia , Nitrilas/farmacologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologiaRESUMO
STUDY DESIGN: Retrospective study. PURPOSE: To investigate the clinical manifestations of a fragility fracture of the sacrum (FFS) and the factors that may contribute to a misdiagnosis. OVERVIEW OF LITERATURE: The number of patients diagnosed with FFS has increased because of extended life expectancy and osteoporosis. Patients with FFS may report nonspecific symptoms, such as back, buttock, groin, and/or leg pain, leading to a misdiagnosis and a delay in definitive diagnosis. METHODS: Fifty-six patients (13 males and 43 females) with an average age of 80.2±9.2 years admitted to the hospital for FFS between 2006 and 2021 were analyzed retrospectively. The following patient data were collected using medical records: pain regions, a history of trauma, initial diagnoses, and rates of fracture detection using radiography, computed tomography (CT), and magnetic resonance imaging (MRI). RESULTS: Forty-one patients presented with low back and/or buttock pain, nine presented with groin pain, and 17 presented with thigh or leg pain. There was no history of trauma in 18 patients (32%). At the initial visit, 27 patients (48%) were diagnosed with sacral or pelvic fragility fractures. In contrast, 29 patients (52%) were initially misdiagnosed with lumbar spine disease (23 patients), hip joint diseases (three patients), and buttock bruises (three patients). Fracture detection rates for FFS were 2% using radiography, 71% using CT, and 93% using MRI. FFS was diagnosed definitively using an MRI with a coronal short tau inversion recovery (STIR) sequence. CONCLUSIONS: Some patients with FFS have leg pain with no history of trauma and are initially misdiagnosed as having lumbar spine disease, hip joint disease, or simple bruises. When these clinical symptoms are reported, we recommend considering FFS as one of the differential diagnoses and performing lumbar or pelvic MRIs, particularly coronal STIR images, to rule out FFS.
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Background: Reverse total shoulder arthroplasty (RSA) has been approved since 2014 in Japan, and the number of RSA cases has been accumulating. However, only short-to medium-term outcomes have been reported, with a small number of case series, because of its short history in Japan. This study aimed to evaluate complications after RSA in hospitals affiliated with our institute, with comparison to those in other countries. Methods: A multicenter retrospective study was performed at 6 hospitals. In total, 615 shoulders (mean age: 75.7 ± 6.2 years; mean follow-up: 45.2 ± 19.6 months) with at least 24 months of follow-up were included in this study. The active range of motion was assessed pre-and postoperatively. The 5-year survival rate was evaluated for reoperation for any reason in 137 shoulders with at least 5 years of follow-up using Kaplan-Meier analysis. Postoperative complications were evaluated, including dislocation; prosthesis failure; deep infection; periprosthetic, acromial, scapular spine, and clavicle fractures; neurological disorders; and reoperation. Furthermore, imaging assessments, including scapular notching, prosthesis aseptic loosening, and heterotopic ossification were evaluated on postoperative radiography at the final follow-up. Results: All range of motion parameters were significantly improved postoperatively (P < .001). The 5-year survival rate was 93.4% (95% confidence interval: 87.8%-96.5%) for reoperation. Complications occurred in 256 shoulders (42.0%), with reoperation in 45 (7.3%), acromial fracture in 24 (3.9%), neurological disorders in 17 (2.8%), deep infection in 16 (2.6%), periprosthetic fracture in 11 (1.8%), dislocation in 9 (1.5%), prosthesis failure in 9 (1.5%), clavicle fracture in 4 (0.7%), and scapular spine fracture in 2 (0.3%). Regarding imaging assessments, scapular notching was observed in 145 shoulders (23.6%), heterotopic ossification in 80 (13.0%), and prosthesis loosening in 13 (2.1%). Conclusion: This is the first large case series to investigate the complications after RSA in Japan, and the overall frequency of complications after RSA was similar to that in other countries.
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The rat mono-iodoacetate (MIA) arthritis model has been used in studies on the hip, knee, and ankle joints. Few studies have explored its utility in shoulder arthritis research, and none have evaluated the effects of time and different MIA doses on arthritis progression. Therefore, we developed a rat MIA shoulder arthritis model to evaluate articular changes through radiological and histological analyses. Sprague-Dawley rats (n = 108) were equally divided into groups that were intra-articularly injected with 0.5 mg of MIA (in 50 µL of purified water), 2.0 mg of MIA (in 50 µL of purified water), or purified water (50 µL; sham group). Throughout the study period, 18 rats (six per group) were evaluated by computed tomography and assessed using the Larsen's classification system; 90 rats were further evaluated histologically using the Osteoarthritis Research Society International scoring system. Computed tomography revealed that the groups injected with MIA developed arthritis and osteophytes 14 days after injection, which progressed temporally. The Larsen's grades worsened over time; at all time points, the scores were higher in the group injected with 2.0 mg of MIA than in the group injected with 0.5 mg of MIA. Furthermore, concurrent with the worsening Larsen's grades, the Osteoarthritis Research Society International scores also significantly increased over time; at all time points, they were higher in the group injected with 2.0 mg of MIA than in the group injected with 0.5 mg of MIA. Our rat MIA shoulder arthritis model revealed radiologically and histologically confirmed temporal and MIA dose-dependent arthritic changes.
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Cartilagem Articular , Osteoartrite , Radiologia , Ratos , Animais , Ratos Sprague-Dawley , Ombro , Osteoartrite/patologia , Água , Modelos Animais de Doenças , Ácido Iodoacético/efeitos adversos , Cartilagem Articular/diagnóstico por imagem , Cartilagem Articular/patologiaRESUMO
BACKGROUND: A comparison of changes in the long head of the biceps tendon for different types of rotator cuff tears has not been previously performed. Furthermore, the correlation between the thickening and degeneration of the long head of the biceps tendon and the cause of these changes have not been fully clarified. We evaluated the relationship between degenerative changes in the long head of the biceps tendon and rotator cuff tears in a rat model using imaging and histology. METHODS: Ninety-six 12-week-old Sprague-Dawley rats were divided into anterior (subscapularis tear), anterosuperior (subscapularis, supraspinatus, and infraspinatus tears), superior (supraspinatus and infraspinatus tears), and control groups. The long head of the biceps tendon was harvested at 4 or 12 weeks postoperatively. The cross-sectional areas of the intra- and extra-capsular components of the tendon were measured using micro-computed tomography, and the affected/normal ratio of the cross-sectional area was calculated. Masson's trichrome staining and Alcian blue staining were performed for histologic analysis, with degenerative changes described using the modified Bonar scale. The correlation between the affected/normal ratio and Bonar scores was evaluated. RESULTS: The affected/normal ratio was higher for the anterior and anterosuperior groups than for the control group at 4 and 12 weeks. The ratio increased for the intra-articular portion in the superior group and for both the intra- and extra-articular portions in the anterior and anterosuperior groups. Degeneration considerably progressed in the anterior and anterosuperior groups compared with the control group from weeks 4 to 12 and was greater in the intra- than in the extra-articular portion. The ratio correlated with extracellular matrix score. CONCLUSIONS: Subscapularis tears were associated with progressive thickening and degeneration of the long head of the biceps tendon at 4 and 12 weeks postoperatively, which was more significant in the intra- than in the extra-articular portion. Histologic evaluation indicated that the extracellular matrix likely caused these degenerative changes.
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Lesões do Manguito Rotador , Ratos , Animais , Lesões do Manguito Rotador/diagnóstico por imagem , Lesões do Manguito Rotador/cirurgia , Lesões do Manguito Rotador/patologia , Microtomografia por Raio-X , Ratos Sprague-Dawley , Tendões/diagnóstico por imagem , Tendões/patologia , Manguito Rotador/diagnóstico por imagem , Manguito Rotador/patologiaRESUMO
Introduction: Magnetic resonance imaging (MRI) is widely used in orthopedics, but orthopedic surgeons, including spine surgeons, do not have detailed knowledge of MRI-related accidents. We, as orthopedic surgeons, investigated the details of medical accidents related to ferromagnetic objects brought into the MRI room using a national multicenter database. Methods: We conducted an exploratory analysis of accidents involving MRI ferromagnets based on the Japanese database of adverse medical occurrences. From a total of 104,659 accident reports over nine years, 172 involving the presence of ferromagnetic objects in the MRI room were extracted and analyzed. Results: The accident reports frequently involved children and the elderly. Nurses filed the highest number of reports (44.8%) by occupation, which was more than twice as many as physicians (19.8%). The most common ferromagnetic devices brought into the MRI rooms were pacemakers (n = 22). There were also large magnetic objects such as oxygen cylinders (n = 12) and IV stands (n = 7). In the field of orthopedics, ankle weights (n = 4), pedometers (n = 3), and artificial limbs (n = 2) were brought in. "Failure to check" was the most common cause of accidents (69%). Actual harm to patients occurred in 9% of cases, with no fatalities. Conclusions: Manuals and checklists should be developed and continuous education provided to prevent accidents involving magnetic objects brought into the MR scanner room. As orthopedic surgeons, including spine surgeons, we should be cautious with emergency, geriatric, and pediatric patients because their information and medical history may not be accurate. We should not overlook equipment commonly found in orthopedic practice such as ankle weights and pedometers.
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Rheumatoid arthritis is an inflammatory autoimmune disease, characterized by autoantibody production, synovial inflammation, and joint destruction. Its pathogenesis is due to environmental factors and genetic backgrounds. Bruton's tyrosine kinase is a cytoplasmic non-receptor tyrosine kinase, expressed in most hematopoietic cell lineages, except T cells and plasma cells, and regulates various immune-related signaling pathways, thereby playing a crucial role in pathogenesis. Thus, inhibiting Bruton's tyrosine kinase may prove beneficial in treating autoimmune diseases. In the present study, we characterized Bruton's tyrosine kinase inhibitor, TAS5315, in vitro and evaluated its therapeutic effects in experimental arthritis models. TAS5315 markedly inhibited Bruton's tyrosine kinase enzyme activity and suppressed the B-cell receptor signaling pathway in Ramos cells. Moreover, it suppressed the expression of CD69, CD86, and MHC class II in mouse B lymphocytes and the production of TNF-α and MIP-1α in mouse macrophages and decreased bone resorption activity in mouse osteoclasts. Furthermore, it ameliorated the pathological changes in two rodent models of collagen-induced arthritis in vivo. TAS5315 improved bone mineral density and bone intensity. Thus, these results suggest that TAS5315 could be a promising therapeutic option for the treatment of rheumatoid arthritis.
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Artrite Experimental , Artrite Reumatoide , Camundongos , Animais , Artrite Experimental/patologia , Tirosina Quinase da Agamaglobulinemia , Roedores , Inflamação/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
BACKGROUND: Ischemic necrosis of the abdominal organs caused by compression of the celiac artery (CA) and superior mesenteric artery (SMA) by the median arcuate ligament (MAL) after correction surgery has been recognized as acute celiac artery compression syndrome (ACACS). Here, using contrast-enhanced computed tomographic (CT) images, we sought to determine the prevalence and degree of CA and SMA stenosis in spinal patients preoperatively, and the risk factors associated with the stenosis. METHODS: We retrospectively examined contrast-enhanced abdominal CT of 90 patients with preoperative lumbar degenerative disease, lumbar burst fracture, or adult spinal deformity. The trunks of the CA and SMA were detected using three-dimensional reconstructed CT. To investigate their degree of stenosis, we determined the ratio of the narrowest diameter of the stenotic segment to the distal normal lumen's diameter. Patients with a degree of stenosis ≥35% were defined as being in the group with stenosis and the remainder as in the group without. To determine the risk factors for stenosis of these arteries, the relationship between the stenosis and CA and SMA calcification or the median arcuate ligament (MAL) crossing the proximal portion of the celiac axis (MAL overlap) was also investigated. RESULTS: The average degree of stenosis of the CA trunk was 12.1% ± 13.9% and that for the SMA trunk was 8.5% ± 8.8%. There were 8 patients (8.9%) in the group with CA stenosis and 2 patients (2.2%) in the group with SMA stenosis. The number of patients in the group with CA stenosis was significantly greater than the number with MAL overlap or CA calcification (P < 0.05). DISCUSSION: The prevalence of CA or SMA stenosis was 11.2% of preoperative patients due to undergo thoracolumbar fusion surgery. Calcifications of the CA trunk and MAL overlap are risk factors for CA stenosis.
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Artéria Celíaca , Artéria Mesentérica Superior , Adulto , Humanos , Artéria Celíaca/diagnóstico por imagem , Artéria Celíaca/cirurgia , Constrição Patológica/cirurgia , Estudos Retrospectivos , Fatores de RiscoRESUMO
Nasal obstruction is one of the most bothersome symptoms of allergic rhinitis (AR) affecting sleep-related quality of life in AR patients. Although several treatments were tested to control nasal obstruction, some patients with moderate to severe AR do not respond to current treatments, including the combined administration of different types of anti-allergic medicine. Thus, new options for AR treatment are needed. This study aimed to evaluate the effects of combined treatment with a novel inhibitor of hematopoietic prostaglandin D synthase (HPGDS), TAS-205, and different types of anti-allergic medicine on nasal obstruction in AR. Firstly, we demonstrated that TAS-205 selectively inhibited prostaglandin D2 (PGD2) synthesis in an enzymatic assay in a cell-based assay and in vivo models of AR. Moreover, treatment with TAS-205 alone suppressed eosinophil infiltration into the nasal cavity and late phase nasal obstruction. The combined administration of TAS-205 with montelukast, a cysteinyl leukotriene receptor 1 antagonist, showed significant additive inhibitory effects on eosinophil infiltration and late phase nasal obstruction compared to treatment with each agent alone. In contrast, concomitant treatment with TAS-205 and fexofenadine, a histamine H1 blocker, showed inhibitory effects on late phase and early phase nasal obstruction, although the magnitude of the inhibitory effects upon combined administration was comparable to that of each single treatment. These results suggest that combined treatment with an HPGDS inhibitor and different types of anti-allergic medicine may be a promising strategy to control nasal obstruction in AR patients.
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Antialérgicos/farmacologia , Inibidores Enzimáticos/farmacologia , Oxirredutases Intramoleculares/antagonistas & inibidores , Lipocalinas/antagonistas & inibidores , Morfolinas/farmacologia , Obstrução Nasal/tratamento farmacológico , Piperidinas/farmacologia , Pirróis/farmacologia , Rinite Alérgica/tratamento farmacológico , Acetatos/farmacologia , Acetatos/uso terapêutico , Animais , Antialérgicos/uso terapêutico , Linhagem Celular , Ciclopropanos/farmacologia , Ciclopropanos/uso terapêutico , Modelos Animais de Doenças , Sinergismo Farmacológico , Quimioterapia Combinada/métodos , Inibidores Enzimáticos/uso terapêutico , Cobaias , Humanos , Oxirredutases Intramoleculares/metabolismo , Lipocalinas/metabolismo , Masculino , Morfolinas/uso terapêutico , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/imunologia , Obstrução Nasal/imunologia , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Piperidinas/uso terapêutico , Prostaglandina D2/metabolismo , Pirróis/uso terapêutico , Qualidade de Vida , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Ratos , Rinite Alérgica/complicações , Rinite Alérgica/imunologia , Sulfetos/farmacologia , Sulfetos/uso terapêutico , Terfenadina/análogos & derivados , Terfenadina/farmacologia , Terfenadina/uso terapêuticoRESUMO
BACKGROUND: Enzalutamide, a second-generation antiandrogen, is an approved medicine for the treatment of metastatic castration-resistant prostate cancer (CRPC); however, the mechanisms behind the resistance are not completely understood. In the present study, we established enzalutamide-resistant cells derived from lymph node carcinoma of the prostate (LNCaP) cells and characterized their androgen receptor (AR) status and changes in the gene expression with an aim to elucidate these mechanisms. METHODS: SAS MDV No. 3-14 enzalutamide-resistant cells were established from LNCaP xenograft castrated male mice under continuous administration of enzalutamide. Then, the AR status and expression of AR target genes were evaluated by western blotting or real-time polymerase chain reaction analysis. The role of AR in the proliferation was also analyzed using the AR siRNA approach. The gene expression profiling in SAS MDV No. 3-14 cells was evaluated by microarray analysis. The role of testis-specific Y-encoded protein (TSPY), one of the upregulated genes, in the expression of AR and AR target genes and cell growth was also verified using siRNA. RESULTS: SAS MDV No. 3-14 cells expressed AR-v7, leading to the increased expression of AR target genes. Gene silencing of AR showed that both AR-FL and AR-v7 function as proliferative drivers in SAS MDV No. 3-14 cells. Microarray analysis revealed that TSPY is upregulated genes in these cells. TSPY siRNA inhibited cell proliferation, decreased the expression of AR-v7 and AR-v7 targeted genes. CONCLUSIONS: This study demonstrated that SAS MDV No. 3-14 cells increase the expression of AR-v7 by upregulating TSPY, leading to acquired resistance to enzalutamide.
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BACKGROUND: Massive rotator cuff tears have a high rate of re-injury because of severe fatty infiltration. Our data showed that injuries proximal to the suprascapular nerve may be one cause of massive rotator cuff tears. The purpose of this study was to evaluate, using a rat model, how brachial plexus injury associated with a massive rotator cuff tear influences healing of the rotator cuff repair. METHODS: Seventy Sprague-Dawley rats were divided into three groups: rotator cuff tear with BP injury (DT group) (n = 28), rotator cuff tear without brachial plexus injury (T group) (n = 28), and a sham-operated group (n = 14). In the DT group, the rotator cuff tear was made and repaired 4 weeks after brachial plexus ligation. The gross assessment (evaluated the wet weight), biomechanical testing (evaluated the yield stress and the Young's modulus) and histological analyses (using the Bonar scale) were performed at baseline in the sham group, and at 4 and 12 weeks postoperatively in the DT and T groups (n = 7/group/time). RESULTS: Mean wet weight and yield stress were significantly lower in the DT group than in the T group. Additionally, the mean Young's modulus was significantly higher in the DT group than in the T group. Histologically, greater tendon degeneration was observed around the musculotendinous junction in the DT group than in the T group. CONCLUSION: The gross, biomechanical and histological data show that the repaired rotator cuff tendon with brachial plexus injury in rats does not heal as well as a repaired tendon without an accompanying brachial plexus injury. This suggests that more proximal neuropathy is one risk factor for re-tear of a repaired rotator cuff tendon.
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Plexo Braquial/lesões , Plexo Braquial/fisiopatologia , Lesões do Manguito Rotador/fisiopatologia , Cicatrização , Animais , Fenômenos Biomecânicos , Modelos Animais de Doenças , Ratos , Ratos Sprague-Dawley , Recidiva , Lesões do Manguito Rotador/cirurgiaRESUMO
A 43-year-old male patient with C5 giant cell tumor (GCT) underwent tumor resection and anterior bone fusion of C4-C6. The tumor recurred locally 9 months after surgery with the patient complaining of neck and shoulder pain similar to his preoperative symptoms. Denosumab was administered and his pain disappeared after a two-month administration, with a sclerotic rim formation seen at the tumor site on computed tomography. He has been followed for 18 months with no evidence of tumor recurrence. Complete resection is generally recommended, but is not easy for many patients with cervical GCT because of the existence of neurovascular structures. Some patients suffer from recurrence and treatment becomes more difficult. As such, denosumab may be an efficacious option for treatment of recurrent GCT of the cervical spine, although long-term follow-up is required to monitor for presence or absence of recurrence.
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We investigated the role of hematopoietic prostaglandin D synthase (H-PGDS) in biphasic nasal obstruction in allergic rhinitis using a new specific inhibitor, (N-methoxy-N-methyl)-4-(5-benzoylbenzimidazole-2-yl)-3,5-dimethylpyrrole-2-carboxamide hydrochloride (TAS-204). First, we developed a novel guinea pig model of allergic rhinitis. Guinea pigs sensitized to ovalbumin without adjuvant were challenged with intranasal exposure to ovalbumin once a week. After the 3rd antigen challenge, they exhibited biphasic nasal obstruction. Additionally, analysis of nasal lavage fluid revealed an increase in the level of prostaglandin D(2) in both early and late phases. Treatment with oral TAS-204 for 15 days during the period of antigen challenges suppressed increases in nasal airway resistance in both phases. It is noteworthy that the late phase nasal obstruction was almost completely abrogated by inhibiting H-PGDS alone. Eosinophil infiltration in nasal lavage fluid and nasal hyperresponsiveness to histamine was also reduced by TAS-204 administration. These findings suggest that H-PGDS plays a critical role in the development of allergic rhinitis, especially in the induction of late phase nasal obstruction.
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Benzimidazóis/farmacologia , Oxirredutases Intramoleculares/metabolismo , Lipocalinas/metabolismo , Obstrução Nasal/enzimologia , Pirróis/farmacologia , Rinite/enzimologia , Animais , Benzimidazóis/uso terapêutico , Dinoprostona/metabolismo , Modelos Animais de Doenças , Eosinófilos/imunologia , Cobaias , Histamina/imunologia , Histamina/metabolismo , Humanos , Oxirredutases Intramoleculares/antagonistas & inibidores , Leucotrienos/metabolismo , Lipocalinas/antagonistas & inibidores , Masculino , Líquido da Lavagem Nasal/imunologia , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/imunologia , Obstrução Nasal/tratamento farmacológico , Obstrução Nasal/imunologia , Obstrução Nasal/metabolismo , Ovalbumina/imunologia , Prostaglandina D2/biossíntese , Prostaglandina D2/metabolismo , Pirróis/uso terapêutico , Rinite/tratamento farmacológico , Rinite/imunologia , Rinite/metabolismo , Fatores de TempoRESUMO
CC-chemokine receptor 3 (CCR3) is a chemokine receptor for which major ligands, CC-chemokine ligand (CCL) 11, CCL24, and CCL26, are known to be involved in chemotaxis for eosinophils. In the present study, we evaluated the effect of a low molecular weight CCR3-receptor antagonist, Ki19003 (4-[[5-(2,4-dichlorobenzylureido)pentyl][1-(4-chlorophenyl)ethyl]amino]butanoic acid), on airway remodeling in a mouse model of allergic asthma. BALB/c mice were sensitized twice by intraperitoneal injection of ovalbumin (OA) and exposed daily to 1% OA for 3 weeks. Twenty-four hours after the final antigen challenge, bronchoalveolar lavage and histological examinations were carried out. Ki19003 clearly inhibited antigen-induced increase in the number of eosinophils in bronchoalveolar lavage fluid (BALF), but did not affect the number of other cell types examined in this study. Ki19003 also inhibited the increased production of transforming growth factor-beta1 in BALF and the amount of hydroxyproline in the lungs in a dose-dependent manner. Furthermore, Ki19003 significantly attenuated allergen-induced subepithelial and peribronchial fibrosis. These findings indicate that CCR3 antagonism prevents not only the infiltration of eosinophils into the airways but also the development of allergen-induced subepithelial and peribronchial fibrosis. Therefore, a CCR3 antagonist may be useful in the treatment of airway remodeling, especially subepithelial and peribronchial fibrosis, in allergic asthma.
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Asma/tratamento farmacológico , Inflamação/tratamento farmacológico , Receptores CCR3/antagonistas & inibidores , Ureia/análogos & derivados , Ácido gama-Aminobutírico/análogos & derivados , Remodelação das Vias Aéreas/efeitos dos fármacos , Animais , Asma/imunologia , Líquido da Lavagem Broncoalveolar/imunologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Eosinofilia/tratamento farmacológico , Eosinofilia/imunologia , Feminino , Hidroxiprolina/metabolismo , Inflamação/imunologia , Pulmão/imunologia , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Fator de Crescimento Transformador beta1/metabolismo , Ureia/administração & dosagem , Ureia/farmacologia , Ácido gama-Aminobutírico/administração & dosagem , Ácido gama-Aminobutírico/farmacologiaRESUMO
BACKGROUND: Nasal polyps are one of the most common findings of physical examination in the otolaryngology area and the experimental model of nasal polyps in the rabbit maxillary sinus is helpful for clarifying the mechanism of polyp formation. Several protocols have been reported for this model, but most of them involved infectious polyps without eosinophil infiltration. We have attempted to establish a novel rabbit model of polyps associated with eosinophil infiltration. METHODS: Rabbits were either untreated (group A) or sensitized with ovalbumin (OVA; groups B-D). After repeated exposure to OVA, some animals further received valine-glycine-serine-glutamine (group C) or poly-L-arginine (group D) in their maxillary sinuses for 4 weeks. Subsequently, sinus tissues were dissected and subjected to histological analysis. The changes in mRNA expression were analyzed by DNA microarray. RESULTS: Remarkable histological changes were observed in groups C and D but not in group B in eosinophil number in the maxillary sinus mucosa, the width of the lamina propria, and polyp scoring. These changes in group D were greater than those in group C. DNA microarray analysis revealed that up-regulated genes in group D included those related to inflammation and extracellular matrix metabolism. On the other hand, down-regulated genes in group D involved those related to anti-inflammation. CONCLUSION: Our results indicate that treatment with inflammatory agents, in combination with an antigen-dependent immune response, could induce nasal polyp formation associated with eosinophil infiltration and mucosal hypertrophy. The gene expression profile supported the clinical relevance of this model.
Assuntos
Eosinofilia/etiologia , Pólipos Nasais/etiologia , Animais , Eosinófilos/patologia , Perfilação da Expressão Gênica , Imunoglobulina G/sangue , Masculino , Mucosa Nasal/patologia , Pólipos Nasais/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Ovalbumina/imunologia , Peptídeos , Reação em Cadeia da Polimerase , CoelhosRESUMO
To clarify the involvement of serine proteases in the development of allergic airway inflammation, we investigated the effect of nafamostat mesilate, a serine protease inhibitor, in a murine model of allergic asthma. Mice were sensitized to ovalbumin (OA) with alum and then exposed to 1% OA for 30 min, three times every 4th day. Nafamostat mesilate was administered orally for 10 days during the allergen challenge. In sensitized mice, repeated allergen challenge induced an increase in tryptase proteolytic activity in bronchoalveolar lavage fluid (BALF). In addition, marked increases in the numbers of inflammatory cells, levels of T helper type 2 (Th2) cytokines and eotaxin in BALF, numbers of goblet cells in the epithelium, and level of OA-specific IgE in serum were observed after repetitive allergen inhalation. Treatment with nafamostat mesilate significantly inhibited not only increased proteolytic activities, but also increases in the numbers of eosinophils and lymphocytes in the BALF. Nafamostat mesilate also dose-dependently inhibited increases in the levels of interleukin-13 and eotaxin in BALF and goblet cell hyperplasia. These findings suggest that increased serine protease activity in the airways is involved in the development of antigen-induced allergic eosinophilic inflammation and epithelial remodeling in bronchial asthma.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Asma/tratamento farmacológico , Eosinófilos/efeitos dos fármacos , Células Caliciformes/efeitos dos fármacos , Guanidinas/farmacologia , Inibidores de Serina Proteinase/farmacologia , Triptases/antagonistas & inibidores , Animais , Asma/enzimologia , Asma/imunologia , Asma/patologia , Benzamidinas , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Quimiocinas/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Eosinófilos/imunologia , Células Caliciformes/enzimologia , Células Caliciformes/imunologia , Células Caliciformes/patologia , Hiperplasia , Imunoglobulina E/sangue , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina , Triptases/metabolismoRESUMO
Asthma is a chronic inflammatory disease characterized by variable bronchial obstruction, hyperresponsiveness, and by tissue damage known as airway remodeling. In the present study we demonstrate that interleukin (IL)-5 plays an obligatory role in the airway remodeling observed in experimental asthma. BALB/c mice sensitized by intraperitoneal injections of ovalbumin and exposed daily to aerosol of ovalbumin for up to 3 wk, develop eosinophilic infiltration of the bronchi and subepithelial and peribronchial fibrosis. The lesions are associated with increased amounts of hydroxyproline in the lungs and elevated levels of eosinophils and transforming growth factor (TGF)-beta1 in the bronchoalveolar lavage fluid. After 1 wk of allergen challenge, TGF-beta is mainly produced by eosinophils accumulated in the peribronchial and perivascular lesions. At a later stage of the disease, the main source of TGF-beta is myofibroblasts, identified by alpha-smooth muscle actin mAb. We show that all these lesions, including fibrosis, are abolished in sensitized and allergen-exposed IL-5 receptor-null mice, whereas they are markedly accentuated in IL-5 transgenic animals. More importantly, treatment of wild-type mice with neutralizing anti-IL-5 antibody, administered before each allergen challenge, almost completely prevented subepithelial and peribronchial fibrosis. These findings demonstrated that eosinophils are involved in allergen-induced subepithelial and peribronchial fibrosis probably by producing a fibrogenic factor, TGF-beta1.