Development Of Inflammatory Infiltrate Research Articles

Treatment of retroperitoneal fibrosis with rituximab, cyclophosphamide and dexamethasone, followed by rituximab and dexamethasone maintenance, achieved disappearance of pathological PET accumulation of FDG and regression of fibrotic masses after 4 months….

Idiopathic retroperitoneal fibrosis is characterized by the development of inflammatory infiltrates with marked fibrosis along the large retroperitoneal vessels. Rituximab in combination with glucocorticoids constitute an effective therapy, but the responses are not long-lasting. In other similar situations, addition of cyclophosphamide to the combination achieved longer and deeper responses. This was the reason to use the triple combination in this case. A 56-year-old man came with four weeks lasting abdominal pain with CT finding of retroperitoneal fibrosis with unilateral ureteral occlusion. Biopsy confirmed retroperitoneal fibrosis with histological findings of IgG4-associated disease. Treatment with prednizone was poorly tolerated. Therefore, the patient was switched to the combination of rituximab 375 mg/m2 on day 1, cyclophosphamide 300 mg/m2 in infusion in days 1 and 15, plus dexamethasone 20 mg in infusion on days 1 and 15, repeated in a 28-day cycle. Fluorodeoxyglucose (FDG) positron emission tomography (PET/CT) examination after 4 months of treatment showed a marked decrease in FDG accumulation and complete disappearance of the fibrotic mass. After 8 months, the induction therapy was followed by maintenance therapy with rituximab 1,000 mg plus dexamethasone 20 mg in 6-month intervals. Control PET/MR examination after 3 years is consistent with complete remission. The number of circulating plasmablasts correlated with the disease activity. Treatment of retroperitoneal fibrosis with the tripple combination of rituximab, cyclophosphamide and dexamethasone achieved a very rapid disappearance of pathological FDG accumulation and fibrotic retroperitoneal mass, with complete disappearance achieved after 4 months of treatment. After 3 years of maitenance therapy, the diesease is still in complete remission on PET/MR examination. We suggest to continue the maintenance therapy with rituximab because of some increase in the number of circulating plasmablasts after prolongation of the intervals between rituximab administration.

Immature myeloid-derived suppressor cells: A bridge between inflammation and cancer (Review).

Chronic inflammation is considered to be one of the hallmarks of tumor initiation and progression. Changes occurring in the microenvironment of progressing tumors resemble the process of chronic inflammation, which begins with ischemia followed by interstitial and cellular edema, appearance of immune cells, growth of blood vessels and tissue repair, and development of inflammatory infiltrates. Moreover, long‑term production and accumulation of inflammatory factors lead to local and systemic immunosuppression associated with cancer progression. Of the several mechanisms described to explain this anergy, the accumulation of myeloid cells in the tumor, spleen, and peripheral blood of cancer patients has gained considerable interest. A population of suppressive CD11b+Gr-1+cells has in fact been designated as myeloid-derived suppressor cells (MDSCs). MDSCs are a unique category of the myeloid lineage, and they induce the prevention of the development of cytotoxic T lymphocytes(CTLs) invitro, and the induction of antigen-specific CD8+T-cell tolerance invivo. Therapeutic approaches directed toward the manipulation of the MDSC population and their function may improve chemoimmune-enhancing therapy for advanced malignancies.

Взаємозв’язок паталогічного ожиріння і хронічного запальної реакції тонкої кишки

Researched biopsy of the small intestine in control person (derived from the injuries of the small intestine) and in the conditions Islands surgical treatment of morbid obesity. In pathological obesity, compared with normal weight, a decrease in villus height, increasing their thickness and deformation. Was noted increase in connective tissue, expand and overflow blood vessels, changes in muscle membrane; also found changing spectrum of white blood cells in the lamina propria of the mucous membrane of the small intestine, increase the relative number of T-lymphocytes and reduction – B-lymphocytes, a significant increase in the number of cells macrophage number and the number of T-helper cells, and more than twice the reduction in the number of T-suppressors. The data is morphological confirmation of negative changes in morbid obesity. That is, the general tendency to enhance inflammatory responses in the body has its manifestations in the small intestine. Thus, the development of pathological obesity accompanied by the development of inflammatory infiltration and connective tissue changes in the state framework and muscular elements in the wall of the small intestine, which in turn is likely to cause breach of the regulation of secretion, absorption and motility of the small intestine.

Sjögren’s Syndrome-Like Ocular Surface Disease in Thrombospondin-1 Deficient Mice

Thrombospondin-1 (TSP-1) is a major activator of latent transforming growth factor-beta in vitro as well as in vivo. Mice deficient in TSP-1, despite appearing normal at birth, develop a chronic form of ocular surface disease that is marked by increased apoptosis and deterioration in the lacrimal gland, associated dysfunction, and development of inflammatory infiltrates that result in abnormal tears. The increase in CD4(+) T cells in the inflammatory infiltrates of the lacrimal gland, and the presence of anti-Sjögren's syndrome antigen A and anti-Sjögren's syndrome antigen B antibodies in the serum resemble autoimmune Sjögren's syndrome. These mice develop an ocular surface disorder dry eye that includes disruption of the corneal epithelial layer, corneal edema, and a significant decline in conjuctival goblet cells. Externally, several mice develop dry crusty eyes that eventually close. The inflammatory CD4(+) T cells detected in the lacrimal gland, as well as those in the periphery of older TSP-1 null mice, secrete interleukin-17A, a cytokine associated with chronic inflammatory diseases. Antigen-presenting cells, derived from TSP-1 null, but not from wild-type mice, activate T cells to promote the Th17 response. Together, these results indicate that TSP-1 deficiency results in a spontaneous form of chronic dry eye and aberrant histopathology associated with Sjögren's syndrome.

Crystal-induced inflammation of the kidneys: results from human studies, animal models, and tissue-culture studies.

Calcium oxalate (CaOx), calcium phosphate (CaP), and uric acid or urate are the most common crystals seen in the kidneys. Most of the crystals evoke an inflammatory response leading to fibrosis, loss of nephrons, and eventually to chronic renal failure. Of the three, CaOx monohydrate is the most reactive, whereas some forms of CaP do not evoke any discernible response. Reactive oxygen species are produced during the interactions between the crystals and renal cells and are responsible for the various cellular responses. CaOx crystals generally form in the renal tubules. Exposure of renal epithelial cells to CaOx crystals results in the increased synthesis of osteopontin, bikunin, heparan sulfate, monocyte chemoattractant protein 1 (MCP-1), and prostaglandin (PG) E2, which are known to participate in inflammatory processes and in extracellular matrix production. CaOx crystal deposition in rat kidneys also activates the renin-angiotensin system. Both Ox and CaOx crystals selectively activate p38 mitogen-activated protein kinase (MAPK) in exposed tubular cells. CaP crystals can form in the tubular lumen, tubular cells, or tubular basement membrane. Renal epithelial cells exposed to brushite crystals produce MCP-1. Basic CaP and calcium pyrophosphate dihydrate induce mitogenesis in fibroblasts, stimulate production of PGE2, and up-regulate the synthesis of metalloproteinases (MMP) while down-regulating the production of inhibitors of MMPs through activation of p42/44 MAPK. Deposition of urate crystals in the kidneys becomes associated with renal tubular atrophy, interstitial fibrosis, and development of inflammatory infiltrate. Renal epithelial cells exposed to uric acid crystals synthesize MCP-1 as well as PGE2. Monocytes or neutrophils exposed to urate crystals produce tumor necrosis factor alpha, interleukin-1 (IL-1), IL-6, and IL-8. Expression of IL-8 is mediated through extracellular signal-regulated kinase 1 (ERK-1)/ERK-2 and nuclear transcription factors activated protein 1 and nuclear factor kappabeta. Urate crystals also stimulate the macrophages to produce MMPs.

1,25-Dihydroxyvitamin D3 inhibits the expression of inducible nitric oxide synthase in rat central nervous system during experimental allergic encephalomyelitis.

The inducible form of nitric oxide synthase (iNOS) generates nitric oxide of which the excessive production is associated with central nervous system (CNS) inflammatory diseases. The investigation of iNOS expression during experimental allergic encephalomyelitis (EAE) of the Lewis rat demonstrated iNOS immunoreactivity and mRNA both during inflammatory bursts (days 12 and 23 post-immunization) and during the remission phase (day 18). iNOS expression was region-specific and expanded with time along a caudo-rostral axis, thus, correlating with the development of inflammatory infiltrates. Whereas cells of the monocyte/macrophage lineage continuously contributed to iNOS expression, astrocytes only expressed iNOS immunoreactivity or mRNA during the relapse (day 23). In order to investigate possible regulatory effects of 1,25-dihydroxyvitamin D3 (1,25-D3) on iNOS expression, rats were treated with the hormone after the beginning of clinical signs (days 11, 13, 19, 21 and 23 post-immunization), and areas of the CNS were examined at day 23. 1,25-D3 exerted a drastic inhibitory effect on iNOS expression, both at the protein and the mRNA levels. However, this effect was region-specific, and was most pronounced in the cerebellum and brainstem, but non-existent in cerebral cortex. iNOS down-regulation occurred in macrophages, activated microglia and astrocytes. The inhibition of iNOS expression in some CNS structures could account for the improvement of clinical signs observed in EAE-rats treated with 1,25-D3. Since 1,25-D3 can be synthesized by activated macrophages or microglia, our results support the hypothesis that this hormone might be implicated in the control of the CNS-specific immune responses. 1,25-D3 or its analogues could, thus, be of therapeutic value in the management of iNOS-associated diseases of the CNS.

Elastase-induced matrix degradation in arterial organ cultures: an in vitro model of aneurysmal disease.

Abdominal aortic aneurysms are characterized by degradation of the extracellular matrix, induction of endogenous metalloproteinases (MMPs), and development of a chronic inflammatory infiltrate. Despite intensive analysis of end-stage tissue, aneurysm pathogenesis remains obscure. The aim of this study was to develop an in vitro model of aneurysmal disease. Porcine aortic organ cultures were preincubated with pancreatic elastase before culture in standard conditions for up to 14 days. The extent of matrix degradation at various time points was determined by quantitative histologic estimation of collagen and elastin concentration. Endogenous metalloproteinase production within the tissue was quantified by gel enzymography and immunoblotting. A separate series of experiments was performed to investigate the effect of incorporating autologous leukocytes into the culture system. Although exogenous elastase was removed after 24 hours, substantial degradation of the aortic extracellular matrix occurred in the subsequent 13 days in tissue culture. Analysis of samples preincubated with elastase (100 U/ml) for 24 hours before tissue culture demonstrated that elastin degradation occurred in a time-dependent manner (p < 0.001) and was not confined to the initial phase of exogenous elastase activity. Gelatin gel enzymography revealed a time-related production of metalloproteinases (55 to 250 kDa) within the aortic tissue. The presence of MMPs-1, 2, 3, and 9 was determined by immunoblotting. Immunohistochemistry identified the vascular smooth-muscle cell as the source of MMPs-1, 2, and 3. Addition of autogenous leukocytes to elastase-pretreated tissue initiated an inflammatory infiltrate within the aortic wall, which further enhanced both matrix degradation and MMP production (p < 0.001). These data demonstrate that aortic samples pretreated with elastase before tissue culture undergo matrix degradation with MMP production and the development of an inflammatory infiltrate. These changes mirror the pathophysiological events within established aneurysms. It is suggested that this model may be useful in understanding early pathogenic events within aneurysmal tissue.

Airway smooth muscle, asthma, and calcium ions

The intracellular concentration of free Ca 2+ ions regulates many functions of cells including secretion, contraction, transport processes, and motility, among others. All of the pathogenetic processes in asthmatic airways are Ca 2+-dependent phenomena: excitation-contraction coupling in smooth muscle, stimulus-secretion coupling in mast cells and mucous glands, nerve impulse initiation and conduction, and the development of inflammatory infiltration. Ca 2+ entry blockers such as nifedipine and verapamil may affect exercise-induced asthma, airway tone, mast cell mediator release, and experimental anaphylaxis. Calmodulin-active drugs can inhibit smooth muscle contraction and mediator release. A new generation of Ca 2+ antagonists may find a role in the management of asthma.