Subacute Inflammation Research Articles

Antiinflammatory, analgesic and antiperoxidative efficacy of Barleria lupulina Lindl. extract

A study was undertaken to investigate the antiinflammatory efficacy of methanol extract of aerial parts of Barleria lupulina Lindl. [MEBL] (Family: Acanthaceae) in acute and sub-acute inflammation models of albino rats. The MEBL in all the tested dose levels exhibited significant inhibition of carrageenin and serotonin induced paw oedema volumes when compared with the untreated (control) group. The MEBL also exerted a significant reduction in granuloma weight in the cotton pellet induced granuloma model. These potentials were comparable to that of the standard drug (indomethacin). The plant extract was also tested for its analgesic, ulcerogenic and antiperoxidative potential. The extract also demonstrated protection against CCl(4) induced lipid peroxidation and acetic acid induced writhing. Acute administration of MEBL (300 mg/kg) did not produce any gastric lesion in rats.

Involvement of tumor necrosis factor-α in sulfur mustard-induced skin lesion; effect of topical iodine

Sulfur mustard (SM), also termed mustard gas, is a potent vesicant that elicits an inflammatory response upon exposure of the skin. Evaluation of mouse ear 3 h after SM exposure revealed acute inflammatory-cell aggregates in the vascular beds accompanied by strongly TNF-alpha-positive neutrophils. Eight hours after SM exposure, this phenomenon became intensified and associated with infiltration into the adjacent dermis. In ear skin topically treated with iodine, however, no inflammatory cells were observed 3 h after SM exposure; 8 h postexposure, blood vessels contained very few TNF-alpha-positive inflammatory cells. Since TNF-alpha induction was shown to be associated with reactive oxygen species production, we studied the effect of iodine on activated peritoneal mouse neutrophils. Iodine elicited a concentration-dependent reduction in the oxidative burst of activated neutrophils. Iodine also scavenged hydroxyl radicals generated by glucose oxidase in a concentration-dependent manner. The involvement of TNF-alpha in SM-induced skin toxicity was confirmed by reduction of 49 and 30% in ear edema following administration of 1 and 2 mug anti-TNF-alpha antibodies, respectively. These findings were corroborated by quantitative analysis of the histological findings showing 46% reduction in acute inflammation and no signs of subacute inflammation in the treated group, in contrast to the control group treated with SM only. Other epidermal (microblister formation, ulceration, and necrosis) and dermal (neutrophilia, hemorrhage, and necrosis) parameters also showed marked reductions in the antibodies-treated group in comparison to controls. The combination of iodine and antiTNF-alpha antibodies might constitute a new approach for treatment of SM-exposed individuals.

Synergistic antiinflammatory effects of pinitol and glucosamine in rats

This study evaluated the antiinflammatory activities of pinitol and glucosamine either alone or in combination against carrageenan- and cotton pellet-induced acute and subacute inflammation in rats. Five groups were included in each of the acute and subacute inflammation studies: the vehicle control group, positive control group (aminopyrine 100 mg/kg), pinitol group (20 mg/kg), glucosamine group (25 mg/kg) and a pinitol (20 mg/kg) and glucosamine (25 mg/kg) combination group. When 20 mg/kg of pinitol was administered to the rats, paw edema induced by the carrageenan injection was significantly suppressed and the level of granuloma formation induced by the cotton pellet implantation was slightly reduced. When 25 mg/kg of glucosamine was administered, paw edema caused by the acute inflammation was slightly reduced and the level of granuloma formation caused by the subacute inflammation was strongly suppressed. Although the combined application of pinitol and glucosamine did not have an additional antiinflammatory effect on the paw edema caused by acute inflammation, it did have an increased antiinflammatory effect on the formation of granuloma induced by subacute inflammation. Therefore, pinitol and glucosamine have an antiinflammatory effect on acute and subacute conditions. Moreover, a synergistic antiinflammatory effect against subacute inflammation was observed when the two chemicals were administered in combination.

Delta analysis of posttransplantation tubulointerstitial damage.

Chronic interstitial fibrosis (CIF) is an adverse prognostic feature of chronic allograft nephropathy. We evaluated the evolution, onset, potential causes, and outcomes of tubulointerstitial damage using 959 protocol kidney biopsy specimens obtained regularly until 10 years after transplantation. Specimens were scored by the Banff schema and analyzed for time-specific change or "delta damage" from sequential biopsy-pairs (n=839). Substantial CIF occurred within 1 year after transplantation, comprising 67.6% of the total burden accumulated during the study period. The maximal intensity of CIF formation occurred within the first 3 months, as a result of acute tubular necrosis and acute and subclinical rejection (all P<0.05), where fibrosis rates exceeded loss from tubular atrophy. By 1 year, diminished CIF formation was accompanied by declining low-level subclinical inflammation (P<0.001) and increasingly prevalent calcineurin inhibitor nephrotoxicity (P<0.01). Banff CIF correlated with tubular atrophy (r=0.82, P<0.001), with tubulointerstitial damage showing a cumulative and irreversible pattern. Mononuclear cell infiltration within areas of tubulointerstitial damage correlated with CIF (r=0.49, P<0.001), tubular atrophy (r=0.43, P<0.001), and Banff i scores (r=0.34, P<0.001) and, most importantly, heralded histologic progression (P<0.001). CIF formation preceded and correlated with glomerulosclerosis (r=0.40, P<0.001), although isotopic glomerular filtration rates underestimated the severity of tubular damage. Cyclosporine (vs. tacrolimus, P<0.001) increased delta CIF, and mycophenolate was protective (vs. azathioprine, P<0.001), independent of their immunosuppressive and nephrotoxic properties when assessed by multivariate analysis of biopsy-pairs (n=849). CIF was a result of early ischemia-reperfusion injury, acute, subacute or persistent interstitial inflammation occurring in a time-dependent manner and was considerably modified by immunosuppressive therapy.

Insulin Receptor Substrate-2-dependent Interleukin-4 Signaling in Macrophages Is Impaired in Two Models of Type 2 Diabetes Mellitus

We have shown previously that hyperinsulinemia inhibits interferon-alpha-dependent activation of phosphatidylinositol 3-kinase (PI3-kinase) through mammalian target of rapamycin (mTOR)-induced serine phosphorylation of insulin receptor substrate (IRS)-1. Here we report that chronic insulin and high glucose synergistically inhibit interleukin (IL)-4-dependent activation of PI3-kinase in macrophages via the mTOR pathway. Resident peritoneal macrophages (PerMPhis) from diabetic (db/db) mice showed a 44% reduction in IRS-2-associated PI3-kinase activity stimulated by IL-4 compared with PerMPhis from heterozygote (db/+) control mice. IRS-2 from db/db mouse PerMPhis also showed a 78% increase in Ser/Thr-Pro motif phosphorylation without a difference in IRS-2 mass. To investigate the mechanism of this PI3-kinase inhibition, 12-O-tetradecanoylphorbol-13-acetate-matured U937 cells were treated chronically with insulin (1 nm, 18 h) and high glucose (4.5 g/liter, 48 h). In these cells, IL-4-stimulated IRS-2-associated PI3-kinase activity was reduced by 37.5%. Importantly, chronic insulin or high glucose alone did not impact IL-4-activated IRS-2-associated PI3-kinase. Chronic insulin + high glucose did reduce IL-4-dependent IRS-2 tyrosine phosphorylation and p85 association by 54 and 37%, respectively, but did not effect IL-4-activated JAK/STAT signaling. When IRS-2 Ser/Thr-Pro motif phosphorylation was examined, chronic insulin + high glucose resulted in a 92% increase in IRS-2 Ser/Thr-Pro motif phosphorylation without a change in IRS-2 mass. Pretreatment of matured U937 cells with rapamycin blocked chronic insulin + high glucose-dependent IRS-2 Ser/Thr-Pro motif phosphorylation and restored IL-4-dependent IRS-2-associated PI3-kinase activity. Taken together these results indicate that IRS-2-dependent IL-4 signaling in macrophages is impaired in models of type 2 diabetes mellitus through a mechanism that relies on insulin/glucose-dependent Ser/Thr-Pro motif serine phosphorylation mediated by the mTOR pathway.

Review of 120 Biopsies Performed on the Balanopreputial Sac

Background: Long-lasting erythematous lesions involving the balanopreputial sac may be clinically difficult to classify, and biopsies may be performed in order to clarify the nature of the disease. However, our previous experience led us to consider several cases as histopathologically unclassifiable. Objective: To establish the causes of such unsatisfactory findings. Methods: We reviewed 120 balanopreputial sac biopsies performed at the surgical unit of our institute from January 1999 to December 2002 examining also the patients’ clinical records. Results: We found that a small group of previously unclassified cases showed common clinical and histopathological features. Clinically, all patients were uncircumcised and had long-lasting asymptomatic erythematous plaques on the balanopreputial sac with no erythroplastic or lichenoid features and no correlation with sexual intercourse. Histologically, all specimens showed a thinned and spongiotic epithelium, a band-like infiltrate of lymphocytes and histiocytes with a variable number of plasma cells in the upper part of the chorion and further signs of acute, subacute or chronic inflammation. Conclusions: In our view, these cases fall within a spectrum of inflammatory non-cicatricial disorders, ranging from almost pure lymphohistiocytic forms to forms which fulfil all criteria to be classified as balanitis circumscripta plasmacellularis of Zoon. We propose to classify these cases histologically as inflammatory non-cicatricial balanoposthitis and clinically as idiopathic inflammatory non-cicatricial balanoposthitis.

Both inflammation and remodeling influence nitric oxide output in children with refractory asthma

Background Exhaled nitric oxide can be used to monitor airway inflammation in asthma. We hypothesized that the strong link between nitric oxide and inflammation may obscure a weaker link with airway remodeling. Objective The aim of this study was to determine whether airway remodeling influenced exhaled nitric oxide in 28 asthmatic children (median age [25th-75th], 11 [10-14] years old) with refractory asthma defined as airflow limitation and/or exacerbations despite high-dose inhaled steroids. Methods Multiple-flow analysis of exhaled nitric oxide was used to correlate alveolar nitric oxide concentration and maximal conducting airway nitric oxide output to pulmonary function tests, bronchoalveolar lavage, and bronchial biopsy findings. Results Nitric oxide measurements were related to inflammation and T H1/T H2 balance, that is, subepithelial eosinophilic infiltration and eosinophilic cationic protein and IFN-γ/IL-4 ratio in bronchoalveolar lavage fluids. Nitric oxide measurements were also correlated with several parameters of airway remodeling: alveolar nitric oxide concentration with TGF-β in bronchoalveolar lavage fluid ( r = 0.42, P = .03) and maximal conducting airway nitric oxide output with reticular basement membrane thickness ( r = 0.61, P = .0007) and tissue inhibitor of matrix metalloproteinases 1/matrix metalloproteinase 9 ratio in bronchoalveolar lavage fluid ( r = 0.43, P = .04). Moreover, alveolar nitric oxide concentration was correlated with MEF 25-75 ( r = 0.60, P = .02). Conclusions These findings suggest that both subacute inflammation and remodeling influence nitric oxide output in refractory asthma.

Investigations of anti-inflammatory and antinociceptive activities of Piper cubeba, Physalis angulata and Rosa hybrida

The anti-inflammatory activities of Piper cubeba (fruit), Physalis angulata (flower) and Rosa hybrida (flower) were determined by carrageenan-induced paw edema, arachidonic acid-induced ear edema and formaldehyde-induced arthritis in mice. The anti-allergic and analgesic activities of these plants were also studied by using 2,4-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity reaction (type IV) and hot plate test in mice, respectively. These plant extracts clearly exhibited inhibitory effects against acute and subacute inflammation by oral administration (200 mg/kg). Also, administration (200 mg/kg, p.o.) of plant extracts for 1 week significantly inhibited type IV allergic reaction in mice ( P<0.05). Rosa hybrida showed an analgesic effect against hot plate-induced thermal stimulation at a dose of 200 mg/kg. These results provide support for the use of Rosa hybrida in relieving inflammatory pain, and insight into the development of new agents for treating inflammatory diseases.

Effect of alcohol extract of Achyranthes aspera Linn. on acute and subacute inflammation.

The antiinflammatory activity of an alcohol extract of Achyranthes aspera was tested on carrageenin-induced hind paw oedema and cotton pellet granuloma models in albino male rats. The paw volume was measured plethysmometrically at 0, 1, 2, 3, 4 and 5 h. In the subacute model cotton pellet granuloma was produced by implantation of 50 +/- 1 mg sterile cotton in the axilla under ether anaesthesia. The animals were fed with an alcohol extract at various dose levels (125, 250, 375 and 500 mg/kg). Diclofenac sodium was used as a standard drug. The alcohol extract (375 and 500 mg/kg) showed the maximum inhibition of oedema of 65.38% and 72.37% at the end of 3 h with carrageenin-induced rat paw oedema, respectively. Using a chronic test, the extract exhibited a 40.03% and 45.32% reduction in granuloma weight.

Studies on the antiinflammatory activity of Betula alnoides bark.

The antiinflammatory activity of Betula alnoides extract was evaluated in acute and subacute inflammation models. The extract was also evaluated for antiinflammatory activity in sheep RBC induced sensitivity and in membrane stabilization models. Except for the sheep RBC induced sensitivity model, the extract showed significant antiinflammatory activity.

Rolipram inhibits leukocyte-endothelial cell interactions in vivo through P- and E-selectin downregulation.

1. Rolipram, a selective phosphodiesterase (PDE) type 4 inhibitor, was used to characterize leukocyte recruitment mechanisms in models of acute and subacute inflammation. Intravital microscopy within the rat mesenteric microcirculation was employed. 2. Mesentery superfusion with PAF (0.1 microM) induced a significant increase in leukocyte rolling flux, adhesion and emigration at 60 min. Rolipram pretreatment, markedly inhibited these parameters by 100, 95 and 95% respectively. 3. Similar effects were observed when the mesentery was superfused with LPS (1 microg ml(-1)) for the same time period and these leukocyte parameters were nearly abrogated by rolipram pretreatment. 4. LPS exposure of the mesentery for 4 h caused a greater increase in leukocyte rolling flux, adhesion and emigration which were inhibited by rolipram administration by 51, 71 and 81% respectively. 5. Immunohistochemistry revealed a significant increase in P-selectin expression after 60 min superfusion with PAF which was attenuated by rolipram. 6. LPS exposure of the mesentery for 4 h caused a significant increase in P- and E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression. Rolipram pretreatment down-regulated both P- and E-selectin expression but had no effect on ICAM-1 and VCAM-1 expression. 7. Significant increases in plasma cyclic AMP levels were detected at 4.5 h after rolipram administration. 8. In conclusion, we have demonstrated that rolipram is a potent in vivo inhibitor of leukocyte-endothelial cell interactions. The effects observed are mediated through endothelial P- and E-selectin downregulation. Therefore, selective PDE-4 inhibitors may be useful in the control of different inflammatory disorders.

EFFECTS OF HCFC-123 EXPOSURE TO MATERNAL AND INFANT RHESUS MONKEYS ON HEPATIC BIOCHEMISTRY, LACTATIONAL PARAMETERS AND POSTNATAL GROWTH

ABSTRACTPeroxisome proliferators are a class of nongenotoxic rodent hepatocarcinogens that cause peroxisome proliferation and liver tumors when administered to rats and mice; but other species, including guinea pigs, dogs, and primates are less sensitive or refractory to the induction of peroxisome proliferation. Therefore, rodent peroxisome proliferators are not believed to pose a hepatocarcinogenic hazard to humans. Some peroxisome proliferators produce developmental toxicity in rats that is expressed as suppressed postnatal growth. To evaluate the relevance of the rat developmental effect to primates, groups of 4 lactating female Rhesus monkeys and their infants were exposed for 6 h/day, 7 days/week for 3 weeks to air or 1000 ppm HCFC-123. Animals were evaluated for clinical signs, body weights, clinical pathology parameters, and biochemical and pathological evaluations of liver biopsy samples. The effect of HCFC-123 exposure on milk quality (protein and fat concentration) was evaluated. The concentrations of HCFC-123 and the major metabolite, trifluoroacetic acid (TFA), were measured in the blood of the mothers and infants and in the milk. Exposure of monkeys to 1000 ppm HCFC-123 did not result in exposure-related clinical observations, or changes in body weight, appetence and behavior. There were no exposure-related effects on serum triglycerides, cholesterol, or glucose levels. HCFC-123 and TFA were present in milk, although maternal HCFC-123 exposure did not affect milk protein and fat content. In general, HCFC-123 was not detected in maternal or infant blood. TFA was detected in the majority of the mothers and TFA levels in infants ranged from 2 to 6 times higher than levels in the corresponding maternal blood. A pharmacokinetic analysis in a maternal animal indicated a peak concentration of TFA at approximately 1 h post-exposure, with a half-life of approximately 20 h. Liver microsomal P450 and peroxisome oxidase activities showed exposure-related decreases in CYP4A1 and CYP2E1 and acyl-CoA oxidase for animals exposed to HCFC-123. Microscopic evaluation of maternal liver from HCFC-123 exposed animals revealed mild to moderate centrilobular hepatocyte vacuolation, trace to mild centrilobular necrosis, and trace to mild subacute inflammation. The histopathological damage and altered hepatic biochemical activities produced by HCFC-123 in monkeys are not consistent with the HCFC-123 peroxisome proliferation response observed in rat livers. These findings demonstrate that HCFC-123 is not a peroxisome proliferator in adult Rhesus monkeys and postnatal exposure to HCFC-123 does not affect body weight of nursing infant monkeys.

Conservative management of appendix mass in children.

The management of an appendix mass in children is controversial. An experience of conservative management of appendix masses in a paediatric population over the last 19 years is reviewed. The medical records of all children who presented with an appendix mass to one of three children's hospitals between 1982 and 2000 were reviewed. In that interval 427 children with a mean age of 7.3 years (range from 2 months to 18 years) presented with an appendix mass. Sixteen children had an immediate appendicectomy. The remaining 411 children were treated conservatively by close observation and antibiotics, with intravenous fluids and nasogastric suction if required. Once the child was well enough for discharge home, elective appendicectomy was booked for 4-6 weeks later. Three hundred and forty-six (84.2 per cent) of the children responded to initial conservative management and were discharged after a median stay of 6 (range 3-24) days. The children returned 4-6 weeks later for elective appendicectomy. The complication rate for elective appendicectomy was 2.3 per cent (eight patients). Those who had an uncomplicated elective appendicectomy had a median hospital stay of 3 (range 1-6) days. Histological examination demonstrated acute or subacute inflammation in 50.8 per cent of appendices removed at elective appendicectomy. Non-operative management of an appendix mass followed by elective appendicectomy is a safe and effective method of management.

Evidence for intraaxonal spread of Listeria monocytogenes from the periphery to the central nervous system.

Rhombencephalitis due to Listeria monocytogenes is characterized by progressive cranial nerve palsies and subacute inflammation in the brain stem. In this paper, we report observations made on mice infected with L. monocytogenes. Unilateral inoculation of bacteria into facial muscle, or peripheral parts of a cranial nerve, induced clinical and histological signs of mainly ipsilateral rhombencephalitis. Similarly, unilateral inoculation of bacteria into lower leg muscle or peripheral parts of sciatic nerve was followed by lumbar myelitis. In these animals, intraaxonal bacteria were seen in the sciatic nerve and its corresponding nerve roots ipsilateral to the bacterial application site. Development of myelitis was prevented by transsection of the sciatic nerve proximally to the hindleg inoculation site. Altogether, our results support the hypothesis that Listeria rhombencephalitis is caused by intraaxonal bacterial spread from peripheral sites to the central nervous system.

Imaging macrophages and the apoptosis of granulocytes in a rodent model of subacute and chronic abscesses with radiolabeled monocyte chemotactic peptide-1 and annexin V.

Monocytes/macrophages (Mphis), the predominant cell types in subacute and chronic inflammation, are attracted to and activated by monocyte chemotactic peptide-1 (MCP-1). Mphis promote the resolution of inflammation through the induction of apoptosis and phagocytosis of senescent (spent) and bystander (superfluous) granulocytes. We wished to determine whether MCP-1, which selectively binds to Mphis, could be used to image subacute and chronic inflammation. We also sought to image granulocyte apoptosis within these lesions with technetium-99m labeled annexin V, a marker of apoptotic cells. Sterile inflammation was induced in 45 12-week-old male Sprague-Dawley rats by deep intramuscular injection of turpentine into the right thigh. Groups of four to six animals were then imaged 1 h after tail vein injection of 37-148 MBq (1-4 mCi) of 99mTc-labeled MCP-1 or annexin V 1-14 days after turpentine treatment. Image analysis showed significantly greater activity of both MCP-1 and annexin V in inflamed thighs than in control thighs (165%-290% and 188%-313%, respectively; P<0.01) on days 1-5 after turpentine injection. Dual autoradiography in animals co-injected with iodine-125 labeled bovine serum albumin on days 1 and 4 showed specific location of MCP-1 to infiltrating Mphis while annexin V localized to focal zones of apoptosis within granulocytic infiltrates adjacent to abscess cavities. Scintillation well counting on day 5 demonstrated significantly higher (P<0.005) ratios of abscess to control thigh specific activities for MCP-1 (5.83+/-2.17) and annexin V (9.24 +/- 2.8) as compared to 125I-labeled bovine serum albumin (3.11 +/- 0.65). No significant increases in uptake were noted at imaging or ex vivo analyses on days 13 and 14, when lesions were predominately fibrotic. It is concluded that 99mTc-labeled MCP-1 and 99mTc-labeled annexin V both localize in zones of subacute inflammation, reflecting the density of Mphis and the incidence of apoptotic granulocytes, respectively. These agents may be useful in the characterization of subacute inflammation.

14-Week toxicity and cell proliferation of methyleugenol administered by gavage to F344 rats and B6C3F1 mice

Methyleugenol, a food flavor and fragrance agent, was tested for toxicity in male and female F344/N rats and B6C3F1 mice. Groups of 10 males and 10 females per sex per species were administered 0, 10, 30, 100, 300 or 1000 mg methyleugenol/kg body weight in 0.5% aqueous methylcellulose by gavage, 5 days per week for 14 weeks. Additional groups of rats and mice of each sex were dosed similarly and used for hematology and clinical chemistry studies. Groups of 10 male and 10 female rats and mice received the vehicle by gavage on the same dosing schedule and served as vehicle controls. For serum gastrin, gastric pH and cell proliferation studies groups of 10 female rats were given 0, 37, 75 or 150 mg/kg, once daily 5 days per week for 30 or 90 days or 300 or 1000 mg/kg for 30 days; male mice were given 0, 9, 18.5, 37, 75, 150 or 300 mg/kg for 30 or 90 days. For the gastrin, pH and cell proliferation studies, groups of 10 female rats and 10 male mice were given the vehicle for 30 or 90 days and served as controls. Methyleugenol administration to rats induced erythrocyte microcytosis and thrombocytosis in male and female rats. It also caused an increase in serum alanine aminotransferase and sorbitol dehydrogenase activities and bile acid concentration, suggesting hepatocellular injury, cholestasis or altered hepatic function. Additionally, methyleugenol induced hypoproteinemia and hypoalbuminemia, evidenced by decreased total protein and albumin concentrations in both male and female rats, suggesting in inefficiency of dietary protein utilization due to methyleugenol-induced toxic effects on the liver and glandular stomach of rats and mice. The increase in gastrin and gastric pH of rats and mice given methyleugenol suggests that gastrin feedback was impaired and resulted in conditions not conducive to protein digestion. In rats, methyleugenol caused an increase in the incidences of hepatocyte cytologic alteration, cytomegaly, Kupffer cell pigmentation, mixed foci of cellular alteration and bile duct hyperplasia of the liver and atrophy and chronic inflammation of the mucosa of the glandular stomach. In mice, it caused an increase in the incidence of cytologic alteration, necrosis, bile duct hyperplasia and subacute inflammation of the liver and atrophy, degeneration, necrosis, edema, mitotic alteration, and cystic glands of the fundic region of the glandular stomach. The increased incidences of adrenal gland cortical hypertrophy and/or cytoplasmic alteration in the submandibular salivary glands, adrenal glands, testis and uterus of rats were considered secondary to the chemical-related effects observed in the liver and glandular stomach. Based on mortality, body weight gain, clinical chemistry and gross and microscopic evaluation of tissues of rats and mice, the no-observed-effect level (NOEL) of methyleugenol for both species was estimated at 10 mg/kg.

Ozone-induced lung inflammation and hyperreactivity are mediated via tumor necrosis factor-alpha receptors.

This study was designed to investigate the mechanisms through which tumor necrosis factor (Tnf) modulates ozone (O(3))-induced pulmonary injury in susceptible C57BL/6J (B6) mice. B6 [wild-type (wt)] mice and B6 mice with targeted disruption (knockout) of the genes for the p55 TNF receptor [TNFR1(-/-)], the p75 TNF receptor [TNFR2(-/-)], or both receptors [TNFR1/TNFR2(-/-)] were exposed to 0.3 parts/million O(3) for 48 h (subacute), and lung responses were determined by bronchoalveolar lavage. All TNFR(-/-) mice had significantly less O(3)-induced inflammation and epithelial damage but not lung hyperpermeability than wt mice. Compared with air-exposed control mice, O(3) elicited upregulation of lung TNFR1 and TNFR2 mRNAs in wt mice and downregulated TNFR1 and TNFR2 mRNAs in TNFR2(-/-) and TNFR1(-/-) mice, respectively. Airway hyperreactivity induced by acute O(3) exposure (2 parts/million for 3 h) was diminished in knockout mice compared with that in wt mice, although lung inflammation and permeability remained elevated. Results suggested a critical role for TNFR signaling in subacute O(3)-induced pulmonary epithelial injury and inflammation and in acute O(3)-induced airway hyperreactivity.

Calcium pyrophosphate dihydrate crystal deposition disease: Imaging perspectives

Calcium pyrophosphate dihydrate (CPPD) crystal is widespread in elderly persons and has various clinical presentation that can be confounding to clinicians. It is characterized by acute, subacute, or chronic joint inflammation and deposition of CPPD crystals in hyaline cartilage, fibrocartilage, and other soft tissue structures. We have learned a great deal about imaging findings of CPPD crystal deposition disease. New facts about the disorder and clues to radiologic diagnosis continue to be revealed. This article will provide a review of imaging characteristics of this disease with emphasis on some recent findings. The nomenclature, epidemiology, classification, and pathophysiology will be explained. A discussion of the clinical manifestations and treatment will be followed by a review of the characteristic imaging features.

Topical Iodine Preparation as Therapy against Sulfur Mustard-Induced Skin Lesions

Sulfur mustard (SM) is a powerful vesicant employed as an agent of chemical warfare. This study demonstrates the therapeutic effect of a novel topical iodine preparation as a postexposure treatment against SM-induced lesions in the fur-covered guinea-pig skin model. Iodine treatment 15 min after SM exposure resulted in statistically significant reductions of 48, 50, and 55% in dermal acute inflammation, hemorrhage, and necrosis, respectively, whereas, the epidermal healing markers, hyperkerathosis and acanthosis, were significantly elevated by 72 and 67%, respectively, 2 days after treatment. At the interval of 30 min between SM exposure and iodine treatment, there was a significant degree of healing or recovery, albeit to a lesser extent than that observed in the shorter interval. Although the epidermal healing markers were not elevated, the parameters indicative of active tissue damage, such as subepidermal microblisters, epidermal ulceration, dermal acute inflammation, hemorrhage, and necrosis, were significantly reduced by 35, 67, 43, 39, and 45%, respectively. At the 45-min interval between exposure and treatment, there was also a certain degree of healing or recovery expressed as significant reductions in dermal subacute inflammation, subepidermal microblister formation, and epidermal ulceration, whereas, acanthosis was statistically elevated, indicating an increased healing potential. At the 60-min interval, iodine was less efficacious; nevertheless, a significant reduction in the incidence of subepidermal microblisters and an expansion of the acanthotic area were observed. Gross ulceration was significantly decreased at intervals of 15 and 30 min between exposure and treatment. The local anesthetic, lidocaine, did not alter the therapeutic effect of iodine. SM was not affected chemically by iodine as measured by gas chromatography-mass spectrometry (GC-MS) analysis. These findings suggest that the iodine preparation functions as an antidote against skin lesions induced by SM.

Blockade of the B7-CD28 pathway by CTLA4-Ig counteracts rejection and prolongs survival in small bowel transplantation.

Allograft rejection involves T-cell activation, requiring T-cell receptor interactions with major histocompatibility complex (MHC) molecules and costimulatory signals delivered through the B7-CD28 pathway. We evaluated the effect of blocking this pathway on graft rejection and survival, in a rat experimental model of small bowel transplantation. Heterotopic small bowel transplantation was performed between PVG donor rats and DA recipient rats. The recipient animals were treated with CTLA4-Ig or irrelevant immunoglobulin (Ig)G as control and followed for 18, 30 or 90 days. The survival rate and degree of inflammation and accumulation of CD4+ T cells and macrophages were determined in the transplanted bowels. We found that administration of CTLA4-Ig significantly improved the survival rate compared to control rats: after 30 days 73% of the treated rats had survived and at 90 days 5/8 rats were still living, whereas in the control group only 2/8 rats had survived. The grafts showed preserved mucosal structure with only a mild degree of subacute inflammation and the accumulation of CD4+ T cells and macrophages was noticeably reduced in treated animals as compared to control rats. Necrosis was extensive in control rats, whereas CTLA4-Ig treated animals had grafts with at least some preserved villus morphology and no necrotic tissue. Although small bowel transplantation has proven exceptionally difficult, in this study we have shown that CTLA4-Ig treatment may provide a promising strategy to prevent rejection and induce long term tolerance and graft survival.