Mechanisms of inflammation and leukocyte chemotaxis in the rheumatic diseases

Understanding the mechanisms of inflammatory cell accumulation, as well as how such cells mediate tissue destruction, provides better insights into the pathogenesis and therapeutics of the rheumatic diseases. This article discusses the role of the inflammatory process in normal immune function, the mechanisms of inflammatory cell accumulation, and how the local accumulation of inflammatory cells can lead to the clinical signs and symptoms associated with rheumatic disorders.     

Effects of clarithromycin on inflammatory cell mediator release and survival

BACKGROUND: Clarithromycin exhibits anti-inflammatory as well as antimicrobial activity, leading to decreased symptoms of asthma and chronic sinusitis. The mode of anti-inflammatory effects of clarithromycin on inflammatory cells is not well understood. We hypothesized that clarithromycin inhibits inflammatory cell mediator release and survival. METHODS: We investigated the effects of this drug on survival and mediator release from mast cells, eosinophils and neutrophils. RESULTS: Human eosinophil and neutrophil respiratory burst was inhibited by up to 54% after 1-2 h pretreatment with 100 microg/ml clarithromycin. Similar doses of erythromycin did not affect respiratory burst responses in these cells. Clarithromycin at doses of up to 100 microg/ml had no effect on granule-derived mediators released from mast cells and neutrophils. However, we found that clarithromycin (100 microg/ml) induced cell death in mast cells and eosinophils after 16-48 h incubation. CONCLUSION: Clarithromycin inhibited inflammatory cell mediator release and survival, which may enhance its ability to reduce the symptoms of chronic sinusitis and asthma.     

喉炎性肌纤维母细胞肿瘤1例报告并文献复习

目的：探讨喉炎性肌纤维母细胞肿瘤的临床病理特点、诊断、治疗、预后。方法：对1例喉IMT进行回顾性分析、免疫组化染色和光镜观察，并进行文献复习。结果：该病临床主要表现为声音嘶哑、发音困难等，确诊主要依靠病理学诊断。肿瘤主要由具有纤维母细胞特征的梭形细胞、慢性炎性细胞组成，Vimentin是最常见的表达。结论：喉IMT是一种罕见的良性肿瘤，有局部浸润和复发的潜能，治疗上以兼顾功能的根治性切除为主，预后良好。     

Identification of DAPI-stained normal,inflammatory, and carcinoma hepatic cells based on hyperspectral microscopy

Gross chromatin imbalance and high DNA content are distinct features of various types of cancer cells. However, severe inflammation can also produce similar symptoms in cells. In this study, normal, inflammatory, and carcinoma hepatic cells were stained with 4’,6-diamidino-2-phenylindole (DAPI) and investigated by hyperspectral microscopy. DAPI is a DNA-sensitive fluorochrome. Therefore, the differences in the cellular DNA of the samples can be revealed by the corresponding fluorescence. Our experimental results demonstrate that although chromosomal disorder and high DNA content both occur in severely inflammatory and carcinoma hepatic cells, there is still a slight difference in their DNA, making their fluorescent intensity and even their spectral shapes distinguishable. Based on these spectral features, we developed a method for the precise identification of normal, inflammatory, and carcinoma hepatic cells in the field of view. The identification accuracy for these three types of cells was 99.8%. We believe that examination that combines DAPI staining with hyperspectral microscopy is a potential method for the identification and investigation of various types of cancer tissues.     

Histopathological diagnosis in gastroesophageal reflux disease

We reviewed the histopathological features for the diagnosis of gastroesophageal reflux disease (GERD). The presence of infiltration inflammatory cells, thickened basal cell layer, increased papillary height was histopathologically evaluated in GERD patients. It is often difficult to diagnose GERD symptoms when there were few endoscopic findings, such as lack of hiatal hernia and erosive esophagitis. At that time, we might be able to diagnose GERD by the histopathological examination except the pH monitor was performed. We showed that the histopathological esophagitis correlated with reflux symptoms and laryngopharyngeal symptoms. These indicated that the histopathological esophagitis may be diagnosed as not only typical GERD but also atypical GERD.     

ABCs of Asthma

Asthma results from chronic airway inflammation involving a diversity of activated cells including mast cells, eosinophils, T-lymphocytes, neutrophils, macrophages, and epithelial cells. These cells release proinflammatory cytokine mediators that augment and regulate airway inflammation, leading to airway hyperresponsiveness responsible for the chronic asthma symptoms of dyspnea, wheezing, and chest tightness. It is hypothesized, but unproven, that inflammatory effects can lead to irreversible structural and functional airway changes. Early intervention with anti-inflammatory agents mitigates inflammatory changes, reverses airway obstruction, and may possibly prevent progression of airway remodeling. Current asthma guidelines recommend that initial management should be based on pretreatment assessments of asthma severity as determined by measures of clinical and spirometric impairment in individual patients; subsequent adjustments of pharmacotherapy and avoidance recommendations should be performed at regular follow-up visits and guided by frequent assessments of asthma control. Physicians and providers should continually educate asthmatic patients about proper use of asthma controller medications, avoidance of asthma triggers, and self-management of asthma exacerbations.     

Systemic Inflammatory Response Syndrome After Administration of Unmodified T Lymphocytes

Systemic inflammatory response syndrome (SIRS) is a rare systemic inflammatory response associated with fever, tachycardia, profound hypotension, and respiratory distress, which has been reported in cancer patients receiving T cells genetically modified with chimeric antigen receptors to retarget their specificity to tumor-associated antigens. The syndrome usually occurs following significant in vivo expansion of the infused cells and has been associated with tumor destruction/lysis. Analysis of patient plasma has shown elevated cytokine levels, and resolution of symptoms has been reported after administration of steroids and/or antibodies (such as anti–tumor necrosis factor and anti-interleukin (IL)-6 receptor antibodies) that interfere with cytokine responses.To date, SIRS has not been reported in subjects receiving genetically unmodified T cells with native receptors directed against tumor antigens, in which greater physiological control of T-cell activation and expansion may occur. Here, however, we report a patient with bulky refractory Epstein-Barr virus (EBV)–associated lymphoma, who developed this syndrome 2 weeks after receiving T cells directed against EBV antigens through their native receptors. She was treated with steroids and etanercept, with rapid resolution of symptoms. SIRS may therefore occur even when T cells recognize antigens physiologically through their “wild-type” native receptors and should be acknowledged as a potential complication of this therapy.     

Traumatic Brain Injury,Neuroinflammation, and Post‐Traumatic Headaches

Concussions following head and/or neck injury are common, and although most people with mild injuries recover uneventfully, a subset of individuals develop persistent post‐concussive symptoms that often include headaches. Post‐traumatic headaches vary in presentation and may progress to become chronic and in some cases debilitating. Little is known about the pathogenesis of post‐traumatic headaches, although shared pathophysiology with that of the brain injury is suspected. Following primary injury to brain tissues, inflammation rapidly ensues; while this inflammatory response initially provides a defensive/reparative function, it can persist beyond its beneficial effect, potentially leading to secondary injuries because of alterations in neuronal excitability, axonal integrity, central processing, and other changes. These changes may account for the neurological symptoms often observed after traumatic brain injury, including headaches. This review considers selected aspects of the inflammatory response following traumatic brain injury, with an emphasis on the role of glial cells as mediators of maladaptive post‐traumatic inflammation.     

Impact of Fungi on Immune Responses

Spores and fungal fragments found in indoor and outdoor environments originate from opportunistic fungi and they can contribute to inflammatory responses, causing a broad range of symptoms. Papers were selected and reviewed with an emphasis on the molecular mechanisms involved in the effect of fungi on immune cells, especially mast cells (MCs). Fungi can bind to antibodies and complement them, allowing them to be recognized by cells of the innate immune system, including macrophages, dendritic cells, and MCs, which are then stimulated via Toll-like receptor signaling. Fungi can cause diseases mediated by MCs and aggravate allergic inflammation. Immunosuppressed subjects can be particularly susceptible to developing diseases caused by opportunistic fungi. Mold also liberates mycotoxins that could be on volatile spores and stimulate MCs to secrete pro-inflammatory cytokines/chemokines, but this mechanism is not known. Fungi can activate the immune system directly or through mycotoxins, leading to stimulation of immune cells and chronic neuroinflammatory symptoms. Some of these processes may be inhibited by the new anti-inflammatory cytokine interleukin 37.     

KCa3.1: target and marker for cancer, autoimmune disorder and vascular inflammation?

KCa3.1 is a calcium-activated intermediate-conductance potassium ion channel. In humans the channel is expressed in several secretory organs and subtypes of hematopoietic cells, but not detected in excitable tissues. The mRNA level for KCa3.1 is upregulated in activated leukocytes, mitogen-induced endothelial cells and vascular smooth muscle cells, and several types of human cancers, suggesting a possible role for the channel in inflammatory and oncology diseases. Several potent and selective KCa3.1 blockers, including clotrimazole and its analogs TRAM-34 and ICA-17043, have been used to investigate the involvement of the channel in human disease. The compounds have been shown to suppress the proliferation of several cancer cells in vitro and the growth of the corresponding cancers in vivo, consistent with an oncologic indication. TRAM-34 also ameliorates symptoms in experimental autoimmune encephalomyelitis and several models of cardiovascular diseases, arguing for a role of the channel in inflammatory diseases. These results suggest several important opportunities for therapeutics based on KCa3.1. Further efforts will establish the optimal indication for these ion channel inhibitors.     

Inflammatory processes in schizophrenia: a promising neuroimmunological target for the treatment of negative/cognitive symptoms and beyond

Emerging evidence indicates that schizophrenia is associated with activated peripheral and central inflammatory responses. Such inflammatory processes seem to be influenced by a number of environmental and genetic predisposition factors, and they may critically depend on and contribute to the progressive nature of schizophrenic disease. There is also appreciable evidence to suggest that activated inflammatory responses can undermine disease-relevant affective, emotional, social, and cognitive functions, so that inflammatory processes may be particularly relevant for the precipitation of negative and cognitive symptoms of schizophrenia. Recent clinical trials of anti-inflammatory pharmacotherapy in this disorder provide promising results by showing superior beneficial treatment effects when standard antipsychotic drugs are co-administered with anti-inflammatory compounds, as compared with treatment outcomes using antipsychotic drugs alone. Given the limited efficacy of currently available antipsychotic drugs to ameliorate negative and cognitive symptoms, the further exploration of inflammatory mechanisms and anti-inflammatory strategies may open fruitful new avenues for improved treatment of symptoms undermining affective, emotional, social and cognitive functions pertinent to schizophrenic disease.     

Airway inflammatory marker]

Since asthma has been recognized as a chronic inflammatory airway disease, inflammatory markers are useful tools to show the degree of allergic airway inflammation. Asthmatic airway is characterized with infiltration of activated Th2 lymphocyte, eosinophils and mast cells/basophils. Eosinophil derived proteins such as ECP, MBP and EDN are important markers indicating eosinophilic inflammation. Histamine and tryptase are the products of mast cell/basophil activation. These markers are detected in sputum, BALF, serum and urine, and increased in asthmatics. In addition to these markers, NO concentration in exhaled air, cytokines such as IL-4, IL-5, chemokines such as RANTES, eotaxin, LTE4, MMP are inflammatory markers to indicate the quality and quantity of asthmatic airway inflammation. Assessment of these markers, therefore, contributes to better control of asthmatic symptoms with appropriate therapy.     

48例术后早期炎性肠梗阻的分析

目的：对术后早期炎性肠梗阻的诊断、治疗和预防进行探讨。方法：回顾分析48例术后早期炎性肠梗阻的临床资料。结果：术后早期炎性肠梗阻多发生在术后6d左右(3～26d)。手术治疗14例，从梗阻症状发作到肠功能恢复的平均时间为11d(5～36d)，平均住院时间为22d(8～60d)；非手术治疗34例，从梗阻症状发作到肠功能恢复的平均时间为6d(1～28d)，平均住院时间为12d(3～38d)。结论：术后早期炎性肠梗阻可表现为典型的肠梗阻症状、体征，采用非手术疗法治疗术后早期炎性肠梗阻效果满意。减少手术创伤及抑制炎症反应对其发生有一定的预防作用。     

The cancer chemotherapy drug etoposide (VP-16) induces proinflammatory cytokine production and sickness behavior-like symptoms in a mouse model of cancer chemotherapy-related symptoms

Cancer chemotherapy-related symptoms such as fatigue, malaise, loss of interest in social activities, difficulty concentrating, and changes in sleep patterns can lead to treatment delays, dose reductions, or termination and have a profound effect on the physical, psychosocial, and economic aspects of quality of life. Clinicians have long suspected that these symptoms are similar to those associated with "sickness behavior," which is triggered by the production of the inflammatory cytokines IL-1beta, TNF-alpha, and IL-6 by macrophages and other cells of the innate immune system in response to immune challenge. The p38 mitogen-activated protein kinase (p38 MAPK) plays a central role in the production of these cytokines and consequently the induction of sickness behavior. Several cancer chemotherapy drugs have been shown to activate p38 MAPK, but whether these drugs can also induce the production of inflammatory cytokines to cause sickness behavior is unknown. The aim of this study was to determine whether the cancer chemotherapy drug etoposide (VP-16), which is known to activate p38 MAPK, could induce inflammatory cytokine production by murine macrophages and sickness-like behaviors when injected into mice. VP-16 activated p38 MAPK and induced IL-6 production in murine macrophages in a p38 MAPK- dependent manner. VP-16 administration rapidly increased serum levels of IL-6 in healthy mice and induced sickness-like behaviors as evidenced by a decrease in food intake, body weight, hemoglobin level, and voluntary wheel-running activity. These findings support the idea that the induction of IL-1beta, TNF-alpha, and IL-6 by cancer chemotherapy drugs underlies the fatigue and associated symptoms experienced by people undergoing cancer chemotherapy.     

Regional CNS responses to IFN-gamma determine lesion localization patterns during EAE pathogenesis

The localization of inflammatory foci within the cerebellum is correlated to severe clinical outcomes in multiple sclerosis (MS). Previous studies of experimental autoimmune encephalomyelitis (EAE), a model of MS, revealed distinct clinical outcomes correlated with the capacity of the animal to produce IFN-gamma. Outcomes were linked to localization of inflammatory cells in either the spinal cord (wild type [WT]) or the cerebellum and brain stem (IFN-gamma deficient). We demonstrate, using an adoptive transfer system, that the ability of the central nervous system (CNS) to sense pathogenic T cell-produced IFN-gamma during EAE initiation determines the sites of CNS pathogenesis. Transfer of WT Th1 cells into IFN-gamma receptor-deficient mice results in pathogenic invasion of the brain stem and cerebellum with attendant clinical symptoms, which are identical to the disease observed after transfer of IFN-gamma-deficient T cells to WT hosts. Inflammation of the spinal cord associated with classical EAE is abrogated in both IFN-gamma-deficient systems. Cotransfer of CNS antigen-specific WT Th1 cells with IFN-gamma-deficient T cells is sufficient to restore spinal cord invasion and block cerebellar and brain stem invasion. These data demonstrate that interaction between IFN-gamma and host CNS cells during the initiation of EAE can selectively promote or suppress neuroinflammation and pathogenesis.     

Comparison of cellular and protein changes in bronchial lavage fluid of symptomatic and asymptomatic patients with red cedar asthma on follow-up examination

Seventeen patients with occupational asthma due to western red cedar had bronchial lavage during follow-up examination after removal from exposure for at least 1 year. Seven patients were asymptomatic while ten continued to have symptoms of asthma requiring treatment. Symptomatic patients had evidence of airway inflammation, as reflected by a significantly higher total cell count, neutrophils and eosinophils, as well as an increase in protein and albumin in their bronchial lavage fluid compared to those without symptoms. Asymptomatic patients had no evidence of airway inflammation in the lavage fluid. There was no correlation between the degree of non-specific bronchial hyperresponsiveness and the number or percentage of inflammatory cells to suggest that cellular infiltration is the sole cause of persistent bronchial hyperresponsiveness.     

慢性黄色肉芽肿性胆囊炎临床及病理分析

目的探讨黄色肉芽肿性胆囊炎(XGC)的临床、超声和病理特征,以提高诊治水平。方法回顾性分析46例确诊病例的临床资料。结果黄色肉芽肿性胆囊炎临床表现与普通慢性胆囊炎相似。胆囊壁不同程度增厚破坏,内壁可见黄色或者棕色斑块。镜下为纤维母细胞,泡沫样组织细胞,急慢性炎细胞组成的肉芽肿改变。结论临床上较难区分黄色肉芽肿性胆囊炎和胆囊癌,确诊必须依靠病理检查。     

Cell therapy for cystic fibrosis

Currently there is no cure for cystic fibrosis (CF). Treatments are focused on addressing the disease symptoms, with varying degrees of success. Regenerative medicine holds the promise of regenerating dysfunctional or damaged tissues and to enhance the body's own endogenous repair mechanisms. The discovery of endogenous and exogenous stem cells has provided valuable tools for development of novel treatments for CF. The ability of stem cells to differentiate into functional pulmonary cells, modulate inflammatory responses and contribute to pulmonary function has provided researchers with multiple approaches to develop effective treatment strategies. Several approaches show promise to produce viable therapeutic treatments to treat the underlying cause of CF, reduce the symptoms and mitigate long‐term damage, and generate functional replacement organs for end‐stage transplantation. This review provides an overview of the rapidly progressing field of cell therapy for CF, focusing on the various cell types utilized and current strategies that show promise to improve life expectancy and quality of life for CF patients. Copyright © 2013 John Wiley & Sons, Ltd.     

窦组织细胞增生伴巨大淋巴结病累及鼻腔临床病理观察

目的探讨窦组织细胞增生伴巨大淋巴结病(SHML)的临床病理特征。方法对1例颈部、鼻腔同时发生SHML的病例进行临床病理分析及免疫组化研究,并进行文献复习。结果颈部淋巴结SHML临床表现为双侧颈部无痛性巨大型淋巴结肿大,镜下病变淋巴结淋巴窦扩张,淋巴窦内充盈淋巴细胞、浆细胞及大量组织细胞,并可见特征性吞噬淋巴细胞、浆细胞或红细胞的组织细胞。鼻腔SHML的临床表现为鼻塞、鼻出血等。镜下病变主要由梭形细胞组成,伴有大量炎细胞浸润,伸入运动不显著。免疫组化显示颈部淋巴结和鼻腔组织细胞S-100和CD68(+),CD1α(-)。结论 SHML可累及鼻腔,诊断主要依赖病理组织学和免疫组化。     

Possible role of inflammatory mediators in tactile hypersensitivity in rat models of mononeuropathy

Peripheral hypersensitivity (hyperalgesia and allodynia) are common phenomena both in inflammatory and in neuropathic pain conditions. Several rat models of mononeuropathy (Bennett, Seltzer and Gazelius models) display such symptoms following partial injury to the sciatic nerve. Using immunohistochemistry and behavioral tests, we investigated inflammatory cell and cytokine responses in the sciatic nerve 14 days after injury created in these different models as well as after axotomy. Tactile hypersensitivity ('allodynia') was present in all Gazelius model rats whereas only 38 and 29% of the Bennett and Seltzer models, respectively, displayed this sign of neuropathy. The inflammatory reactions in rats with and without tactile allodynia were compared. Monocytes/macrophages (ED-1), natural killer cells, T lymphocytes, and the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), were significantly upregulated in all nerve injured rats in comparison to sham-operated controls. Interestingly, ED-1-, TNF-alpha- and IL-6-positive cells increased more markedly in allodynic Bennett and Seltzer rats than in non-allodynic ones. The magnitude of the inflammatory response does not seem to relate to the extent of damage to the nerve fibers because axotomized rats displayed much lower upregulation. Our findings indicate that the considerable increase in monocytes/macrophages induced by a nerve injury results in a very high release of IL-6 and TNF-alpha. This may relate to the generation of tactile allodynia/hyperalgesia, since there was a clear correlation between the number of ED-1 and IL-6-positive cells and the degree of allodynia. It is possible that measures to reduce monocyte/macrophage recruitment and the release of pro-inflammatory interleukins after nerve damage could influence the development of neuropathic pain.