Laser treatment of keloids: a clinical trial and an in vitro study with Nd:YAG laser

Biochemical studies utilizing keloid fibroblast cultures revealed that Nd:YAG laser selectively suppressed collagen production by these cells. Based on these in vitro observations, eight patients with keloids were treated with Nd:YAG laser in a nondestructive manner. Results, with a 3-year follow-up, indicated flattening and softening of the lesions. Thus, the results suggest that Nd:YAG laser is an effective treatment modality for keloids, and its mechanism may involve bioinhibition of fibroblast functions.     

手术切除联合注射曲安奈德加放疗治疗瘢痕疙瘩的疗效观察

目的：评估手术切除联合术中注射曲安奈德加术后早期放射治疗瘢痕疙瘩的疗效。方法：110例患者随机分为对照组和治疗组,对149处瘢痕疙瘩全部行手术切除,治疗组术中在切缘处皮肤真皮内注射曲安奈德,术后24h内对手术部位行放射治疗。结果：术后切口均为I期愈合,术后随访12～24个月,治疗组治愈率为83．6％,与对照组58．2％相比较,P〈0．05。结论：手术切除瘢痕疙瘩,术中注射曲安奈德加早期术后放疗能够有效提高瘢痕疙瘩的治愈率。     

Decreased neuropeptide release may play a role in the pathogenesis of nasal polyps.

In this in vivo prospective, controlled study, we have examined the capsaicin-induced levels and secretion patterns of the colocalized neuropeptides substance P, calcitonin gene-related peptide (CGRP), and neurokinin A in nasal secretions of subjects with nasal polyps, and we compared these with secretion patterns from healthy subjects and from subjects with allergic rhinitis. Capsaicin was used to elicit neuropeptide release. The neuropeptide levels were measured by an ELISA technique. For substance P, subjects with nasal polyps responded very poorly to capsaicin stimulation. The atopic group was more reactive to capsaicin stimulation than control subjects. For CGRP the increase was immediate in all groups. Atopic subjects and subjects with polyps had a less pronounced but sustained response to capsaicin stimulation. CGRP levels in atopic subjects and those with polyps were restored rapidly. Atopic subjects had higher neurokinin A levels with an immediate and sustained response to capsaicin. Control subjects had higher levels than those with polyps, but both groups were nonresponsive to capsaicin stimulation.     

Regulatory Mechanisms for Adipose Tissue M1 and M2 Macrophages in Diet-Induced Obese Mice

OBJECTIVE

To characterize the phenotypic changes of adipose tissue macrophages (ATMs) under different conditions of insulin sensitivity.

RESEARCH DESIGN AND METHODS

The number and the expressions of marker genes for M1 and M2 macrophages from mouse epididymal fat tissue were analyzed using flow cytometry after the mice had been subjected to a high-fat diet (HFD) and pioglitazone treatment.

RESULTS

Most of the CD11c-positive M1 macrophages and the CD206-positive M2 macrophages in the epididymal fat tissue were clearly separated using flow cytometry. The M1 and M2 macrophages exhibited completely different gene expression patterns. Not only the numbers of M1 ATMs and the expression of M1 marker genes, such as tumor necrosis factor-α and monocyte chemoattractant protein-1, but also the M1-to-M2 ratio were increased by an HFD and decreased by subsequent pioglitazone treatment, suggesting the correlation with whole-body insulin sensitivity. We also found that the increased number of M2 ATMs after an HFD was associated with the upregulated expression of interleukin (IL)-10, an anti-inflammatory Th2 cytokine, in the adipocyte fraction as well as in adipose tissue. The systemic overexpression of IL-10 by an adenovirus vector increased the expression of M2 markers in adipose tissue.

CONCLUSIONS

M1 and M2 ATMs constitute different subsets of macrophages. Insulin resistance is associated with both the number of M1 macrophages and the M1-to-M2 ratio. The increased expression of IL-10 after an HFD might be involved in the increased recruitment of M2 macrophages.Obesity and insulin resistance are closely associated with a state of low-grade inflammation in adipose tissue, where resident macrophages play important roles (1–9). Adipose tissue macrophages (ATMs) consist of at least two different phenotypes (i.e., classically activated M1 macrophages and alternatively activated M2 macrophages). A recent report (10) proposed that M1 or M2 ATMs are distinguished by the presence or the absence of CD11c, an M1 macrophage marker. M1 ATMs produce proinflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, and monocyte chemoattractant protein (MCP)-1, thus contributing to the induction of insulin resistance (11–13). On the other hand, M2 ATMs, which are the major resident macrophages in lean adipose tissue, are reported to have a different gene expression profile, characterized by the relatively high expression of CD206, arginase-1, MglI, and IL-10, which are involved in the repair or remodeling of tissues (10–14).Recent studies have demonstrated the involvement of M1/M2 ATMs in the regulation of insulin sensitivity. The deletion of M1 marker genes such as TNF-α (15) and C-C motif chemokine receptor (CCR) 2 (8) or the ablation of CD11c-positive cells resulted in the normalization of insulin sensitivity (16). On the other hand, the mice with the macrophage-specific knockout of peroxisome proliferator–activated receptor (PPAR) γ or PPARβ/δ displayed insulin resistance with reduced number and impaired function of M2 macrophages (17–20). The latter studies also indicated that IL-4 or IL-13 from adipocytes or hepatocytes promotes the expression of PPARγ and PPARβ/δ in monocytes, resulting in the differentiation of M2 macrophages. Although it is generally accepted that M1 ATMs induce insulin resistance by secreting a variety of proinflammatory cytokines, how M2 ATMs contribute to the amelioration of insulin resistance is currently unknown.Recently, Lumeng et al. (10) used CD11c as an M1 marker in a flow cytometry analysis and reported that high-fat diet (HFD)-induced obesity causes a shift in ATMs from an M2 polarized state in lean animals to an M1 proinflammatory state. However, the precise mechanism of how the increased ratio of M1 macrophages is induced in diet-induced obese mice is not fully understood (e.g., are M1 macrophages newly recruited from circulating monocytes, or do M2 macrophages present in lean adipose tissue differentiate into M1 macrophages?)To evaluate the changes in the number as well as the gene expression of M1 and M2 markers more precisely, we analyzed mouse ATMs by flow cytometry using CD206 as an M2 marker in addition to using CD11c as an M1 marker. Here, we show that the CD11c-positive/CD206-negative M1 ATMs and the CD206-positive/CD11c-negative M2 ATMs constituted distinct populations. The number of M1 macrophages and the M1-to-M2 ratio are related to the development of insulin resistance. Interestingly, the overexpression of IL-10 by adenovirus vector increased the markers of M2 ATMs in adipose tissue, suggesting that enhanced IL-10 expression by an HFD and/or pioglitazone treatment may be involved in a phenotypic switch in ATMs.     

Do circulating factors play a role in the pathogenesis of minimal change nephrotic syndrome?

This review examines the studies which have been undertaken to test the hypothesis that minimal change nephrotic syndrome of childhood (MCNS) is a primary immune disorder and that there is altered T-cell function which results in release of a circulating factor. This factor alters glomerular permeability, perhaps by modifying charge sites in the glomerular capillary bed, and results in selective proteinuria. The abnormalities in immune function observed in MCNS are summarized, as are the studies of circulating factors which have been identified. Although some agents have been shown to alter capillary permeability, the unequivocal demonstration of such a factor causing selective proteinuria in vivo, either directly or indirectly, is lacking. The question is raised whether intrarenal release or activation of mediators of altered permeability, rather than the systemic release of such factors, may be important in the pathogenesis of MCNS.     

Autonomic nervous system appears to play a role in obliteration of processus vaginalis

Background: Failed obliteration of processus vaginalis (PV) has recently been proposed to be due to persistence of the smooth muscle (SM), which is transiently present to generate the physical force to descend the testis. Sacs from hernia, hydrocele, or undescended testis reveal alterations in Ca²⁺ contents. Since Ca²⁺ signaling and some regulatory proteins are involved in programmed cell death (PCD), a flow cytometric evaluation was planned to evaluate the expression of inducers or inhibitors of PCD in sacs from different diagnostic sources. Methods: Sacs associated with male hernia (n=16), female hernia (n=11), undescended testis (n=9), and hydrocele (n=11) were evaluated for binding of annexin and expressions of Bcl-2, Bax, Fas, Fas-ligand (Fas-L), and Fas+Fas-L. The binding and expressions in cells that express -smooth muscle actin (-SMA) were also determined. Expressions according to the groups were compared through unpaired t-test, and P values less than 0.05 were considered to be significant. Results: Sacs associated with undescended testis that contain the least SM revealed the most annexin binding, and sacs associated with hernia that contain the most SM binded the least annexin. However, expressions of Bcl-2, Bax, Fas, Fas-L and Fas+Fas-L have not revealed a significant difference. On the other hand, Bax and Fas expressions of cells that express -SMA have been significantly higher in sacs associated with undescended testis. Conclusions: Since increase of Bax and Fas in cells that express -SMA are encountered in sacs with the least SM content, Bax and Fas appear to play roles in the amount of persisting SM. The necessities of initial depletion of Ca²⁺ stores through inositol 1,4,5-trisphosphate receptors and subsequent increase of Bax and Fas levels in the mitochondrial pathway of PCD, together with the role of the sympathetic system in maintenance of SM, suggest a determinative role of the autonomic nervous system for obliteration of PV.     

The predominance of M2-polarized macrophages in the stroma of low-hypoxic bladder tumors is associated with BCG immunotherapy failure

ObjectiveBacillus Calmette-Guérin (BCG) immunotherapy is the gold standard treatment for superficial bladder tumors with intermediate/high risk of recurrence or progression. However, approximately 30% of patients fail to respond to the treatment. Effective BCG therapy needs precise activation of the type 1 helper cells immune pathway. Tumor-associated macrophages (TAMs) often assume an immunoregulatory M2 phenotype and may directly interfere with the BCG-induced antitumor immune response. Thus, we aim to clarify the influence of TAMs, in particular of the M2 phenotype in stroma and tumor areas, in BCG treatment outcome.Patients and methodsThe study included 99 patients with bladder cancer treated with BCG. Tumors resected before treatment were evaluated using immunohistochemistry for CD68 and CD163 antigens, which identify a lineage macrophage marker and a M2-polarized specific cell surface receptor, respectively. CD68⁺ and CD163⁺ macrophages were evaluated within the stroma and tumor areas, and high density of infiltrating cells spots were selected for counting. Hypoxia, an event known to modulate macrophage phenotype, was also assessed through hypoxia induced factor (HIF)-1α expression.ResultsPatients in whom BCG failed had high stroma-predominant CD163⁺ macrophage counts (high stroma but low tumor CD163⁺ macrophages counts) when compared with the ones with a successful treatment (71% vs. 47%, P = 0.017). Furthermore, patients presenting this phenotype showed decreased recurrence-free survival (log rank, P = 0.008) and a clear 2-fold increased risk of BCG treatment failure was observed in univariate analysis (hazard ratio = 2.343; 95% CI: 1.197–4.587; P = 0.013). Even when adjusted for potential confounders, such as age and therapeutic scheme, multivariate analysis revealed 2.6-fold increased risk of recurrence (hazard ratio = 2.627; 95% CI: 1.340–5.150; P = 0.005). High stroma-predominant CD163⁺ macrophage counts were also associated with low expression of HIF-1α in tumor areas, whereas high counts of CD163⁺ in the tumor presented high expression of HIF-1α in tumor nests.ConclusionsTAMs evaluation using CD163 is a good indicator of BCG treatment failure. Moreover, elevated infiltration of CD163⁺ macrophages, predominantly in stroma areas but not in the tumor, may be a useful indicator of BCG treatment outcome, possibly owing to its immunosuppressive phenotype.     

M2-macrophage infiltration and macrophage traits of tumor cells in urinary bladder cancer

Background

Tumor-associated macrophages (TAMs) constitute a subset of nonneoplastic cells in tumor stroma and influence cancer progression in solid tumors. The clinical significance of TAMs in urinary bladder cancer (UBC) is controversial.

胃癌组织中HIF-1α,CD68及CD206在胃癌及癌旁组织中的表达及临床意义

目的 分析低氧诱导分子-1α（HIF-1α）及肿瘤相关巨噬细胞（TAM）相关抗原CD68、CD206在胃癌及癌旁组织中的表达情况。方法 利用免疫组化技术检测43例胃癌和癌旁组织中HIF-1α、CD68、CD206的表达状态,计算三种蛋白表达的阳性率及阳性细胞数,揭示其与临床因素的相关性。结果 HIF-1α、CD68、CD206的阳性表达率分别为58.1%、69.8%、51.2%,均高于癌旁组织（P<0.05）。胃癌、癌旁组织中每个视野下CD68⁺细胞数分别为（39.7±7.6）、（8.5±2.8）个;CD206⁺阳性细胞数分别为（32.0±9.2）、（3.4±1.8）个;HIF-1α⁺细胞数（22.9±5.6）、（2.1±1.2）个;组间比较差异均有统计学意义（P<0.01）。胃癌组织中CD206⁺细胞数与HIF-1α⁺细胞数表达呈正相关（P<0.01,R²=0.641）。三种蛋白的表达与胃癌病理分期、淋巴结转移明显相关（P<0.05）。结论 胃癌组织中CD68、CD206、HIF-1α表达率及阳性细胞数明显增加,且CD206与HIF-1α表达呈正相关。胃癌缺氧区域对M2型巨噬细胞有趋化作用,促进胃癌发生发展。     

手术切除加激素注射治疗胸前瘢痕疙瘩

目的：探讨胸前瘢痕疙瘩的有效治疗方法。方法：采用手术切除加瘢痕区激素注射治疗64块胸前瘢痕疙瘩。结果：64块瘢痕疙瘩变为线状或萎缩性瘢痕，随诊1～6年，均获良好控制。结论：手术切除加激素辅助治疗胸前瘢痕疙瘩安全高效，易为多数医生和患者所接受。     

Macrophages play a role in the early phase of corneal allograft rejection in rats

BACKGROUND: Rat corneal allograft rejection is delayed by repeated local injection of liposomes filled with clodronate (dichloromethylene diphosphonate), which selectively deplete macrophages. Various administration schedules of liposomes were tested to determine the optimum schedule for prevention of graft rejection. Cell subpopulations in the anterior segment of the eye were studied at different time points after transplantation to assess the kinetics of the immune response. METHODS: AO rats were grafted orthotopically with corneal buttons from PVG rats. Postoperatively, rats remained untreated or received clodronate liposomes subconjunctivally. Clodronate liposomes were injected five times on postoperative days (PODs) 0, 2, 4, 6, and 8; or once, on POD 0 or 6; or twice on PODs 0 and 2 or PODs 0 and 6. Grafts were examined for signs of rejection clinically and immunohistologically. RESULTS: All untreated rats rejected their grafts as did all five rats that received clodronate liposomes once on POD 6. In all the other administration schedules tested, graft survival was prolonged compared with the untreated control group (P <0.01). Injections of clodronate liposomes on PODs 0 and 2 proved to be the most effective treatment. Histologically reduced influx of virtually all cell types tested was found in this group. CONCLUSIONS: To prevent or delay graft rejection, it is necessary to administer clodronate liposomes in the early phase after corneal transplantation. These results suggest a role for macrophages in the afferent phase of corneal graft rejection.     

滑膜巨噬细胞在骨性关节炎发病机制中的作用及其潜在性应用研究进展

骨性关节炎是一种全世界范围内发病率高的慢性退行性疾病,其病理特征为关节软骨退化和软骨下骨结构改变并伴有滑膜炎症和骨赘形成。虽然该病的研究取得了一些进展成果,但其确切的病因及发病机制仍不完全清楚。滑膜巨噬细胞作为关节滑膜中重要的炎症细胞,其不同的极化状态在骨性关节炎的发病中起着重要作用。巨噬细胞受其所处不同微环境的刺激时极化为具有促炎作用的M1型巨噬细胞和抗炎作用的M2型巨噬细胞,促使未极化的巨噬细胞向M2型极化或调控M1型巨噬细胞向M2型转化,对抑制骨性关节炎的发展起到积极作用。笔者通过查阅近几年相关研究文献,就滑膜巨噬细胞在骨性关节炎发病机制中的作用及其潜在性应用展开综述,为后期骨性关节炎的诊治及研究提供新的思路和方向。