IL6 trans-signaling promotes functional recovery of hypofunctional phagocytes through STAT3 activation during peritonitis

Objective

The role of high interleukin 6 (IL6) levels has not been clearly explained in severe sepsis. We show that the augmentation of the IL6 signal by recombinant IL6 receptors (rIL6R) delivery allows the functional recovery of phagocytes in a peritonitis mouse model.

Materials and Methods

Mice were challenged intraperitoneally (i.p.) with live Staphylococcus aureus for effect of IL6R delivery on the 24 h-survival, bacterial clearance and cellular responses. In additional experiments to assess the effect of IL6R delivery on phagocytosis, the model was i.p. inoculated with heat-killed S. aureus with or without rIL6R and the peritoneal lavage fluid and cells were collected at 1 h after the i.p. inoculation of S. aureus.

Results

The IL6R delivery tended to improve 24 h survival and increase bacteria clearance from the septic mice. The rIL6R treatment to heat-killed bacteria challenged mice augmented the uptake of bacteria and phagosome acidification, inducing the phosphorylation of STAT3 in peritoneal cells within 1 h after the IL6R delivery. Furthermore, the rIL6R delivery prevented the extracellular release of neutrophil elastase activity and myeloperoxidase (harmful factors).

Conclusions

These results indicate that augmentation of IL6 signaling appears to be critical for the effective management of hypofunctional neutrophils during severe inflammation, such as sepsis.     

New guiding catheter for transrad PTCA

A new guiding catheter for PTCA is described. In our department, 302 patients (405 lesions) underwent transradial coronary angioplasty using the 6 Fr Kimny guiding catheter since January 1996. The total engagement rate using the Kimny guiding catheter was 91.3% (370/405). The engagement rate after the modified Kimny guiding catheter was introduced in May 1996 increased to 96.0% (243/253). The stent delivery success rate was 98.4%. We had two dislodged stents. PTCA for both left and right coronary arteries in a single procedure with the Kimny guiding catheter was performed via the radial artery in 27 patients. In 24 of these patients (89%) we engaged both coronaries successfully. In the remaining 3 patients we switched to another catheter. Except for 4 patients with non-Q-wave myocardial infarction, no major cardiac complications were encountered. No major entry site-related complications were seen, and no patient required vascular surgery or blood transfusions. In one patient the Kimny guiding catheter tip caused a minor dissection of the LMT, but no ischemic event occurred as a result. In conclusion, the Kimny device is a useful PTCA guiding catheter for routine angioplasty and stenting. Cathet. Cardiovasc. Diagn. 43:344–351, 1998. © 1998 Wiley-Liss, Inc.     

Poly(I:C) reduces expression of JAM-A and induces secretion of IL-8 and TNF-α via distinct NF-κB pathways in human nasal epithelial cells

Human nasal epithelium is an important physical barrier and innate immune defense protecting against inhaled substances and pathogens. Toll-like receptor (TLR) signaling, which plays a key role in the innate immune response, has not been well characterized in human nasal epithelial cells (HNECs), including the epithelial tight junctional barrier. In the present study, mRNAs of TLR1-10 were detected in hTERT-transfected HNECs, which can be used as an indispensable and stable model of normal HNECs, similar to primary cultured HNECs. To investigate the changes of tight junction proteins and the signal transduction pathways via TLRs in HNECs in vitro, hTERT-transfected HNECs were treated with TLR2 ligand P₃CSK₄, TLR3 ligand poly(I:C), TLR4 ligand LPS, TLR7/8 ligand CL097, TLR8 ligand ssRNA40/LyoVec, and TLR9 ligand ODN2006. In hTERT-transfected HNECs, treatment with poly(I:C) significantly reduced expression of the tight junction protein JAM-A and induced secretion of proinflammatory cytokines IL-8 and TNF-α. Both the reduction of JAM-A expression and the induction of secretion of IL-8 and TNF-α after treatment with poly(I:C) were modulated by distinct signal transduction pathways via EGFR, PI3K, and p38 MAPK and finally regulated by a TLR3-mediated NF-κB pathway. The control of TLR3-mediated signaling pathways in HNECs may be important not only in infection by viral dsRNA but also in autoimmune diseases caused by endogenous dsRNA released from necrotic cells.     

Ramp rate of blood pressure changes does not affect aortic afferent sensitivity in anesthetized rats

To investigate whether the rate of change in blood pressure affects the sensitivity of the aortic baroreceptor afferent response, the change in aortic nerve activity (ANA) to two different rates of ramp increase in mean blood pressure (MBP), elicited by phenylephrine administration, was determined in the rat under urethane (1.5 g kg⁻¹) anesthesia. The sensitivity of the increase in ANA following a rapid (average ramp rate, 9.14 ± 0.60 mmHg s⁻¹, n = 11) or gradual (1.78 ± 0.24 mmHg s⁻¹, n = 11) increase in MBP was 2.03 ± 0.14% and 1.81 ± 0.20% of baseline mmHg⁻¹, respectively. These values were not significantly different from each other (P = 0.16). Furthermore, we found no correlation between the rate of ramp increase in MBP and the sensitivity of the increase in ANA (r = 0.24, P = 0.29, n = 22). These results suggest that, at least within the normal physiological range of MBP, the rate of the ramp change in blood pressure does not affect aortic baroreceptor afferent sensitivity in the anesthetized rat.     

Age-dependent change in activities of lysosomal enzymes in rat brain

The age-dependent change in activities of seven lysosomal enzymes (cathepsin D, β-glucuronidase, acid phosphatase, acid/alkaline DNases and acid/alkaline RNases) was studied in four brain regions (cerebrum, hippocampus, pons and cerebellum) of Wistar rats. The activity of cathepsin D was significantly increased with aging in the four regions. The age-dependent change in activities of acid and alkaline DNases showed the characteristic regional difference, and the ratio of acid to alkaline DNases was increased with aging in all regions. Acid RNase showed the lowest activity in 18-month-old rats, and alkaline RNase activity was decreased with aging. The activity of β-glucuronidase was higher in 2-month-old rats in all of the regions studied. Acid phophatase showed no significant age-dependent change except in pons. The study demonstrated that all of the lysosomal enzyme activities do not change in parallel with aging, and that the age-dependent change showed the characteristic regional difference.     

Proximal dome-shaped osteotomy for symptomatic bunionette

The results of a dome-shaped osteotomy of the proximal third of the fifth metatarsal in patients with symptomatic bunionette deformity were reviewed. The series was comprised of eight patients (10 feet; mean age of patients, 21 years). The average followup was 30 months. All patients were free from pain at the fifth metatarsophalangeal joint and were satisfied with the results of this procedure. The mean angle between the longitudinal axes of the fifth metatarsal and the proximal phalanx was 18.9 degrees before surgery and 2.6 degrees after surgery. The mean angle between the longitudinal axes of the fourth and fifth metatarsals was 12.2 degrees before surgery and 4.8 degrees after surgery. The overall results were good in all 10 feet. Three feet had delayed union at the osteotomy site, but union was obtained in all feet. The osteotomy site of the fifth metatarsal in feet with delayed union was more proximal than that of the other feet. Therefore, proximal osteotomy of the fifth metatarsal should be done not at the base, but at the proximal site of the diaphysis to prevent delayed union. A proximal dome-shaped osteotomy corrects the deformity and relieves the symptoms, but careful attention should be paid to the osteotomy site.     

Clinical significance of vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 in patients with nonsmall cell lung carcinoma

BACKGROUND: Vascular endothelial growth factor C (VEGF-C) plays an important role in lymphangiogenesis and activates VEGF receptor 3 (VEGFR-3). By contrast, lymphatic spread is an important prognostic factor in patients with nonsmall cell lung carcinoma (NSCLC). The objective of the current study was to determine whether the expression of VEGF-C and VEGFR-3 correlates with clinicopathologic factors and prognosis in patients with primary NSCLC. METHODS: The authors conducted a retrospective review of 180 consecutive patients who underwent complete resection for NSCLC and who did not receive any chemotherapy or radiotherapy prior to surgery. Immunohistochemical staining for VEGF-C and VEGFR-3 was performed. The clinicopathologic implications of VEGF-C and VEGFR-3 expression were analyzed statistically. RESULTS: Of 180 patients with NSCLC, 137 patients (76.1%) were positive for VEGF-C, and 40 patients (22.2%) were positive for VEGFR-3. VEGF-C expression was observed frequently in patients with adenocarcinoma (P = 0.026). For VEGFR-3 expression, significant correlations were demonstrated with age (P = 0.02), gender (P = 0.008), and histologic differentiation in patients with squamous cell carcinoma (P = 0.03). Patients who had positive staining for VEGF-C showed significantly less favorable survival rates compared with patients who had negative staining for VEGF-C (P = 0.003). The survival rates of patients who had positive staining for VEGFR-3 also were significantly lower compared with patients who had negative staining for VEGFR-3 (P < 0.001). Patients who had positive staining for both VEGF-C and VEGFR-3 exhibited the most unfavorable prognoses. Univariate analysis revealed the following prognostic factors: gender (P = 0.03), tumor status (T1,T2 vs. T3; P < 0.01), lymph node status (negative vs. positive; P < 0.01), tumor size (< or = 35 mm vs. > 35 mm; P < 0.01), disease stage (Stage I vs. Stages II and III; P < 0.01), VEGF-C expression (negative vs. positive; P < 0.01), VEGFR-3 expression (negative vs. positive; P < 0.01) and combined VEGF-C and/or VEGFR-3 expression (both positive vs. VEGF-C or VEGFR-3 positive; P < 0.01). Multivariate analysis demonstrated that VEGFR-3 expression was the only independent negative prognostic factor (P < 0.01). CONCLUSIONS: VEGF-C and VEGFR-3 expression may be indicative of survival rates for patients with NSCLC.     

Brain-derived neurotrophic factor-mediated retrograde signaling required for the induction of long-term potentiation at inhibitory synapses of visual cortical pyramidal neurons

High-frequency stimulation (HFS) induces long-term potentiation (LTP) at inhibitory synapses of layer 5 pyramidal neurons in developing rat visual cortex. This LTP requires postsynaptic Ca²⁺ rise for induction, while the maintenance mechanism is present at the presynaptic site, suggesting presynaptic LTP expression and the necessity of retrograde signaling. We investigated whether the supposed signal is mediated by brain-derived neurotrophic factor (BDNF), which is expressed in pyramidal neurons but not inhibitory interneurons. LTP did not occur when HFS was applied in the presence of the Trk receptor tyrosine kinase inhibitor K252a in the perfusion medium. HFS produced LTP when bath application of K252a was started after HFS or when K252a was loaded into postsynaptic cells. LTP did not occur in the presence of TrkB-IgG scavenging BDNF or function-blocking anti-BDNF antibody in the medium. In cells loaded with the Ca²⁺ chelator BAPTA, the addition of BDNF to the medium enabled HFS to induce LTP without affecting baseline synaptic transmission. These results suggest that BDNF released from postsynaptic cells activates presynaptic TrkB, leading to LTP. Because BDNF, expressed activity dependently, regulates the maturation of cortical inhibition, inhibitory LTP may contribute to this developmental process, and hence experience-dependent functional maturation of visual cortex.     

A clinicopathological study of ameloblastomas

72 cases of ameloblastoma were obtained from the files of the Department of Pathology, School of Dentistry, Aichi-Gakuin University for the years January 1970 through December 1983. The cases were analyzed with respect to sex, age, duration, site histopathology, and treatment. Of 72 patients, 63 had no previous therapy, while 9 received their initial treatment elsewhere. There were 38 males and 34 females, a ratio of 1.2: 1. At the time of diagnosis, the ages of all patients ranged from 11 to 71 years, with an average of 36.6 years. About 65% of patients were in the 2nd, 3rd, and 4th decades of life. The duration of symptoms varied from 2 days to 5 years, with an average of 12.6 months. 69 cases occurred in the mandible, with the molar-ramus region being the most frequent site of involvement. Only 3 were found in the maxilla. The left side of the mandible was affected 1.6 times more frequently than the right. Histopathologically, 44 cases were of the plexiform type, 15 the follicular, 10 the acanthomatous, and 2 the basal cell type. Only 1 case was of the granular cell type. Most of the findings in the present study agreed with previous available data from the literature on ameloblastomas.