Pathology of lumbar nerve root compression. Part 1: Intraradicular inflammatory changes induced by mechanical compression.

STUDY DESIGN: This study is to investigate the intraradicular inflammation induced by mechanical compression using in vivo model. OBJECTIVES: The relationship between the intraradicular edema and nerve fiber degeneration induced by mechanical compression was determined in the nerve root. SUMMARY OF BACKGROUND DATA: Recently some studies reported that mechanical compression increased microvascular permeability of the endoneurial capillaries and resulted in an intraradicular inflammation. These changes may be an important factor of the pathogenesis of radiculopathy. However, the natural courses of the intraradicular inflammation after mechanical compression are still poorly understood. METHODS: In dogs, laminectomy was performed at L7 and the seventh nerve root was exposed to compression at 7.5 gram force (gf) clipping power. The animals were evaluated at 1 and 3 weeks after clipping. After the appropriate period of nerve root compression, Evans blue albumin (EBA) was injected intravenously. The nerve root sections were divided into two groups. The sections were used to investigate the status of the blood-nerve barrier function under the fluorescence microscope. The other sections were used for light and transmission electron microscopic study. RESULTS: After 1 and 3 weeks, intraradicular edema was observed not only at the site of compression but also in the peripheral zone of a compressed anterior root and in the central zone of a compressed posterior root. The evidence of active Wallerian degeneration was also seen in the area of intraradicular edema. In addition, the nerve roots showing Wallerian degeneration were infiltrated by inflammatory cells, such as macrophages and mast cells. CONCLUSIONS: Inflammatory reaction, such as Wallerian degeneration, breakdown of blood-nerve barrier and appearance of macrophage, may be deeply involved in radiculitis arising from mechanical compression, and these factors seem to be important in the manifestation of radiculopathy.     

Involvement of receptor activator of NFkappaB ligand and tumor necrosis factor-alpha in bone destruction in rheumatoid arthritis

Bone loss represents a major unsolved problem in rheumatoid arthritis (RA). The skeletal complications of RA consist of focal bone erosions and periarticular osteoporosis at sites of active inflammation, and generalized bone loss with reduced bone mass. New evidence indicates that osteoclasts are key mediators of all forms of bone loss in RA. TNF-alpha is one of the most potent osteoclastogenic cytokines produced in inflammation and is pivotal in the pathogenesis of RA. Production of tumor necrosis factor-alpha (TNF-alpha) and other proinflammatory cytokines in RA is largely CD4(+) T-cell dependent and mostly a result of interferon-gamma (IFN-gamma) secretion. Synovial T cells contribute to synovitis by secreting IFN-gamma and interleukin (IL)-17 as well as directly interacting with macrophages and fibroblasts through cell-to-cell contact mechanisms. Activated synovial T cells express both membrane-bound and soluble forms of receptor activator of NF-kappaB ligand (RANKL). In rheumatoid synovium, fibroblasts also provide an abundant source of RANKL. Furthermore, TNF-alpha and IL-1 target stromal-osteoblastic cells to increase IL-6, IL-11, and parathyroid hormone-related protein (PTHrP) production as well as expression of RANKL. In the presence of permissive levels of RANKL, TNF-alpha acts directly to stimulate osteoclast differentiation of macrophages and myeloid progenitor cells. In addition, TNF-alpha induces IL-1 release by synovial fibroblasts and macrophages, and IL-1, together with RANKL, is a major survival and activation signal for nascent osteoclasts. Consequently, TNF-alpha and IL-1, acting in concert with RANKL, can powerfully promote osteoclast recruitment, activation, and osteolysis in RA. The most convincing support for this hypothesis has come from in vivo studies of animal models. Protection of bone in the presence of continued inflammation in arthritic rats treated with osteoprotegerin (OPG) supports the concept that osteoclasts mediate bone loss, providing further evidence that OPG protects bone integrity by downregulating osteoclastogenesis and promoting osteoclast apoptosis. Modulation of the RANKL/OPG equilibrium in arthritis may provide additional skeletal benefits, such as chondroprotection. The nexus between T-cell activation, TNF-alpha overproduction, and the RANKL/OPG/RANK ligand-receptor system points to a unifying paradigm for the entire spectrum of skeletal pathology in RA. Strategies that address osteoclastic bone resorption will represent an important new facet of therapy for RA.     

Pathophysiology of disk-related sciatica. I.--Evidence supporting a chemical component

Sciatica in patients with disk disease was long ascribed to pressure put on the sciatic nerve root by a herniated disk. However, a role for chemical factors acting in conjunction with this mechanical insult is suggested by a number of clinical observations: disk surgery does not consistently provide pain relief, large disk herniations are not always symptomatic, severe pain may be present in patients without imaging evidence of nerve root compression, the severity of symptoms and neurological signs is not well correlated with the size of the disk herniation, and conservative therapy is often effective. Experimental studies have provided further evidence for a chemical component: disk herniations can undergo spontaneous resorption, the intervertebral disk is immunogenic, and mediators for inflammation have been identified within intervertebral disk tissue. The current pathophysiological theory incriminates proinflammatory substances secreted by the nucleus pulposus (NP). When preexisting or concomitant mechanical injury to a nerve root occurs, these substances can cause nerve root pain. Animal experiments have established that the NP can induce functional and structural nerve root abnormalities in the absence of mechanical compression and that this effect is mediated by substances located at the surface of NP cells. Methylprednisolone, diclofenac, indomethacin, doxycycline, and cyclosporine induce variable inhibition of this effect. Available information points to tumor necrosis factor-alpha (TNF-alpha) as the main candidate among substances potentially responsible for nerve root pain. Therefore, trials of TNF-alpha antagonists in patients with disk-related sciatica are warranted.     

Compressive neuropathy of spinal nerve roots. A mechanical or biological problem?

Pathophysiologically, nerve root pain production is a complex issue. For many years, mechanical compression has been regarded as the sole cause for such pain. There are indications, however, that other factors, such as intraneural inflammation, may be of importance in this context. In this article, four cases are presented in which nerve root related pain gradually resolved without any proven change in the mechanical deformation of the involved nerve root. The data presented here suggest that mechanical compression, per se, may not always be the sole cause of radicular pain and dysfunction. These findings suggest that improvement is needed in our understanding of the pathophysiology of nerve root compression and inflammation.     

Influence of pro-inflammatory (IL-1 alpha,IL-6, TNF-alpha,IFN-gamma) and anti-inflammatory (IL-4) cytokines on chondrocyte function

OBJECTIVE: Cytokines produced by inflammatory cells play a pivotal role in synovial inflammation and joint destruction in rheumatoid arthritis. To investigate the influence of pro-inflammatory cytokines (IL-1 alpha, IL-6, TNF-alpha, IFN-gamma) and subsequently the possible beneficial role of an anti-inflammatory cytokine (IL-4) on chondrocyte viability (necrosis/apoptosis), proliferation and nitric oxide (NO) production. METHODS: Primary bovine chondrocytes were cultured until monolayers were obtained. Cells were incubated with cytokines (IL-1 alpha, IFN-gamma, TNF-alpha, IL-4, IL-6) at 0.1, 1, 10 and 100 ng/mL. After 48 h, the viability of the chondrocytes was measured flow cytometrically with propidium iodide. Proliferation was determined by the incorporation of tritiated thymidine. The morphology of the chondrocytes, including presence of apoptotic nuclei, was evaluated by a May-Grünwald-Giemsa staining. In addition, the number of apoptotic chondrocytes was detected flow cytometrically with a TUNEL technique and annexin-V/propidium iodide staining. NO production was evaluated using a spectrophotometric assay, based upon the Griess reaction. RESULTS: The viability and proliferation of bovine chondrocytes decreased after incubation with 100 ng/mL IL-1 alpha, TNF-alpha or IFN-gamma. In contrast, incubation of chondrocytes with IL-4 or IL-6 had no influence on the viability or the proliferation of cells. IL-1 alpha was able to enhance NO production in a dose dependent manner. IFN-gamma and TNF-alpha induced NO production only at the highest concentration (100 ng/mL), whereas IL-4 and IL-6 did not. There was a dose dependent increase in apoptosis of bovine chondrocytes cultured in the presence of IL-1 alpha and TNF-alpha. This effect could not be prevented by preincubation with IL-4. Preincubation with IL-4 diminished IL-1 alpha and TNF-alpha induced NO production and increased proliferation of chondrocytes. In an additional experiment, incubation of human chondrocytes with anti-Fas did not induce apoptosis as measured by annexin-V/propidium iodide staining. CONCLUSIONS: Pro-inflammatory cytokines are able to induce apoptosis, whereas IL-4 as an anti-inflammatory cytokine can inhibit the effect of IL-1 alpha and TNF-alpha on NO production and proliferation of bovine chondrocytes.     

热休克因子1基因转染对烧伤血清刺激的巨噬细胞炎性介质表达的影响

目的了解外源性热休克因子1（HSF1）对烧伤血清刺激的巨噬细胞中相关炎性介质基因表达的影响。方法制备严重烧伤和正常大鼠血清；构建pcDNA3．1／HSF1重组载体。将培养的RAW264．7巨噬细胞株转染（具体分为：未转染、转染空载体、转染重组载体）后再分别使用前述2种血清刺激。另取部分未行血清刺激的转染重组载体的巨噬细胞，用蛋白质印迹法检测其HSF1蛋白表达水平；反转录-PCR法检测经血清刺激的细胞中肿瘤坏死因子α（TNF-α）、高迁移率族蛋白B1（HMGB1）和白细胞介素10（IL-10）基因表达水平。结果已转染重组载体的细胞株较稳定，检出有HSF1部分活化。反转录-PCR检测到，未转染的正常血清刺激的巨噬细胞中TNF—α、HMGB1、IL-10的基因仅有少量表达，而烧伤血清刺激能明显上调其基因表达（分别为0．910±0．100、0．860±0．020、0．430±0．010）；与转染空载体＋烧伤血清组（上述3项指标分别为0．800±0．050、0．880±0．030、0．420±0．010）比较，转染重组载体＋烧伤血清组可明显抑制巨噬细胞中TNF—α和HMGB1的基因表达并上调IL-10的基因表达（分别为0．130±0．100、0．450±0．020、0．450±0．020）。结论严重烧伤后给予HSF1可以抑制巨噬细胞产生的某些促炎介质的表达，适当上调某些抗炎介质的表达，对机体发挥保护作用。     

Pathoanatomy and pathophysiology of nerve root compression

The anatomy and physiology of the nerve root complex in the lumbar spine are reviewed, with special reference to the effects of mechanical deformation of nerve roots in association with intervertebral disc herniation and spinal stenosis. Biomechanical aspects of nerve root deformation induced by compression are discussed. The functional changes induced by compression can be caused by mechanical nerve fiber deformation but also may be a consequence of changes in nerve root microcirculation, leading to ischemia and formation of intraneural edema. Nerve root compression can, by different neurophysiologic mechanisms, induce motor weakness and altered sensibility or pain. Intraneural edema and demyelination seem to be critical factors for the production of pain in association with nerve root compression.     

Agonist of peroxisome proliferator-activated receptor-gamma, rosiglitazone, reduces renal injury and dysfunction in a murine sepsis model.

BACKGROUND: Agonists of the peroxisome proliferator-activated receptor-gamma may help to regulate inflammation by modulating the production of inflammatory mediators and adhesion molecules. The purpose of this study was to determine the protective effects of rosiglitazone on renal injury in a sepsis model and to explore the mechanism. METHODS: In lipopolysaccharide (LPS)-induced mouse sepsis, we examined the effect of rosiglitazone on LPS-induced overproduction of inflammatory mediators, on the expression of adhesion molecules in renal tubular epithelial cells and on renal function. The mechanism of the protective effect was investigated in vitro using human renal tubular epithelial cells. RESULTS: Rosiglitazone significantly decreased serum tumour necrosis factor (TNF)-alpha and interleukin (IL)-1beta levels during sepsis. The levels of blood urea nitrogen and creatinine were significantly lower in mice pre-treated with rosiglitazone than that in LPS-treated mice. Rosiglitazone reduced the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in tubular epithelial cells and interstitium of LPS-treated mice. Pre-treatment with rosiglitazone reduced the infiltration of macrophages/monocytes in renal tissue. In cultured tubular epithelial cells, rosiglitazone significantly decreased the expression of ICAM-1 and VCAM-1 induced by TNF-alpha or IL-1beta, inhibited the degradation of inhibitor kappaBalpha (IkappaBalpha) and blocked the activation of the p65 subunit of nuclear factor (NF)-kappaB. CONCLUSIONS: These results indicate that pre-treatment with rosiglitazone attenuated the production of TNF-alpha and IL-1beta and reduced adhesion molecule expression in renal tubular epithelial cells of LPS-treated mice. Rosiglitazone has an anti-inflammatory effect in renal tubular epithelial cells through the inhibition of NF-kappaB activation.     

Understanding the biology of compressive neuropathies

Compressive neuropathies are highly prevalent, debilitating conditions with variable functional recovery after surgical decompression. Chronic nerve compression injury induces concurrent Schwann cell proliferation and apoptosis in the early stages of the disorder, independent of axonal injury. These proliferating Schwann cells locally demyelinate and remyelinate in the region of injury. Furthermore, Schwann cells upregulate vascular endothelial growth factor secondary to chronic nerve compression injury and induce neovascularization to facilitate the recruitment of macrophages. In contrast to Wallerian degeneration, macrophage recruitment occurs gradually with chronic nerve compression injury and continues for a longer time. Schwann cells change their gene and protein expression in response to mechanical stimuli as shear stress decreases the expression of myelin associated glycoprotein and myelin basic protein mRNA and protein for in vitro promyelinating Schwann cells. The local down-regulation of myelin associated glycoprotein in the region of compression injury creates an environment allowing axonal sprouting that may be reversed with intraneural injections of purified myelin associated glycoprotein. These studies suggest that while the reciprocal relationship between neurons and glial cells is maintained, chronic nerve compression injury is a Schwann cell-mediated disease.     

What are the local and systemic biologic reactions and mediators to wear debris, and what host factors determine or modulate the biologic response to wear particles?

New clinical and basic science data on the cellular and molecular mechanisms by which wear particles stimulate the host inflammatory response have provided deeper insight into the pathophysiology of periprosthetic bone loss. Interactions among wear particles, macrophages, osteoblasts, bone marrow-derived mesenchymal stem cells, fibroblasts, endothelial cells, and T cells contribute to the production of pro-inflammatory and pro-osteoclastogenic cytokines such as TNF-alpha, RANKL, M-SCF, PGE2, IL-1, IL-6, and IL-8. These cytokines not only promote osteoclastogenesis but interfere with osteogenesis led by osteoprogenitor cells. Recent studies indicate that genetic variations in TNF-alpha, IL-1, and FRZB can result in subtle changes in gene function, giving rise to altered susceptibility or severity for periprosthetic inflammation and bone loss. Continuing research on the biologic effects and mechanisms of action of wear particles will provide a rational basis for the development of novel and effective ways of diagnosis, prevention, and treatment of periprosthetic inflammatory bone loss.     

Cytotoxicity in glioma cells due to interleukin-12 and interleukin-18-stimulated macrophages mediated by interferon-gamma-regulated nitric oxide

OBJECT: Interleukin (IL)-12 and IL-18 synergistically mediate antitumor responses through the production of interferon-gamma (IFNgamma) by T and natural killer (NK) cells. Recently, it has been reported that macrophages stimulated with these cytokines also produce IFNgamma, which led the authors to investigate the antiglioma activity of macrophages stimulated by the combination of these cytokines in vitro. METHODS: Dish-adherent peritoneal exudate cells, which had been elicited in thioglycollate broth as a source of macrophages, were used in the experiment. The murine glioma cell lines VM-glioma and 203G were labeled with [3H]thymidine for a cytotoxicity assay of macrophages. In response to the combined stimulation by IL-12 and IL-18, macrophages expressed potent cytotoxic activity against glioma cells in association with increasing production of IFNgamma and nitric oxide (NO). Inhibitors of NO abrogated the cytotoxic activity of the macrophages, which had been induced by IL-12 and IL-18, despite the increase in IFNgamma production. Neutralization of IFNgamma or use of macrophages obtained from IFNgamma gene-knockout mice markedly reduced not only cytotoxic activity, but also NO production. Depletion of T and NK cells from the macrophage population, which was achieved using antibody plus complement treatment, slightly reduced macrophage activities, suggesting that these are the main effector cells, although T and NK cells may partially participate in this cytotoxicity. CONCLUSIONS: Macrophages stimulated with IL-12 and IL-18 produced IFNgamma and NO, which in turn mediated the antiglioma response. Therefore, macrophages as well as T and NK cells play an important role in antitumor responses stimulated by IL-12 and IL-18.     

Pain and the immune system: friend or foe?

When tissue is destroyed, pain arises. Tissue destruction as well as wound healing are associated with an inflammatory reaction. This leads to activation of nociceptors ("pain receptors") which can cross-communicate with the inflammatory infiltrate. The following review will concentrate on pain-exaggerating (hyperalgesic) and pain-ameliorating (analgesic) mediators which arise from immune cells or the circulation during the inflammation. In the early stages of inflammation endogenous hyperalgesic mediators are produced, including the proinflammatory cytokines IL-1, IL-6 and TNF-alpha, nerve growth factor as well as bradykinin and prostaglandins. Simultaneously, analgesic mechanisms are activated. Opioid peptides such as endorphins, enkephalins and dynorphins are produced by immune cells and can be released locally in the inflamed tissue on stimulation with IL-1 or corticotropin releasing factor. Analgesia is elicited by binding of the opioid peptides to receptors on peripheral sensory neurons. During the course of an inflammatory process, peripheral opioid-mediated analgesia increases. In parallel, antiinflammatory cytokines such as IL-4, IL-10, IL-13 and IL-1ra are produced and reduce hyperalgesic effects of the proinflammatory cytokines initially produced. Inflammatory pain, therefore, is the result of an interplay between hyperalgesic and analgesic mediators. Drugs such as immunosuppressants influencing this interplay may also impair endogenous hyperalgesic and analgesic mechanisms.     

Glucosamine HCl alters production of inflammatory mediators by rat intervertebral disc cells in vitro.

BACKGROUND CONTEXT: Studies on cartilage have shown anti-inflammatory effects of glucosamine related to inhibition of inflammatory mediators. Intradiscal injection of glucosamine has been proposed as a treatment for chronic discogenic low back pain. However, there have been no studies of the direct effects of glucosamine on disc cells. PURPOSE: To determine the effects of glucosamine HCl on pro-inflammatory mediator production by intervertebral disc cells. STUDY DESIGN: An in vitro, experimental study of interleukin-1 (IL-1) stimulated rat intervertebral disc cells treated with and without glucosamine HCl. METHODS: Rat annulus and nucleus cells were cultured in alginate beads and exposed to IL-1a (10 ng/mL)+glucosamine HCl (4.5 mg/mL), IL-1 alone, or neither for 4 and 7 days. Cell viability and IL-6, tumor necrosis factor alpha (TNF-alpha), prostaglandin E(2) (PGE(2)), and NO levels in the medium were quantified and compared across treatments. RESULTS: Annulus cells, 7 days: Glucosamine completely inhibited IL-6 and TNF-alpha, increased NO (by 75%), and reduced viability (by 89%) compared with IL-1 alone. Nucleus cells, 7 days: Glucosamine reduced IL-6 (by 89%), PGE(2) (91%), and NO (90%) with no effect to viability. CONCLUSIONS: Glucosamine inhibits inflammatory mediator production by IL-1 stimulated disc cells, but also adversely affects the viability of rat annulus cells. The response is cell-type dependent, illustrated by differences for annulus and nucleus cells.     

Expression of nitric oxide and inducible nitric oxide synthase in acute renal allograft rejection in the rat

BACKGROUND: Recent studies have shown that nitric oxide (NO) synthases, particularly inducible nitric oxide synthase (i-NOS), are induced in acute rejection episodes following heart, liver, pancreas and kidney allotransplantation. Furthermore, tissue and cellular injury has been demonstrated to be mediated by peroxynitrite (ONOO-), a metabolite of NO as well as a potent oxidant. However, a detailed relationship between NO, i-NOS and graft injury in transplantation remains elusive. METHODS: The present study used the following models of renal transplantation in rats: allografts (n = 5, Brown-Norway to Lewis [LEW] rats), isografts (n = 5, LEW to LEW) and allografts treated with aminoguanidine (AG), an i-NOS inhibitor (n = 5). Blood urea nitrogen (BUN), serum creatinine (SCr) and urinary and serum nitrosocompounds (NOx) were measured on days 2, 4 and 7 post-transplant. Western blot analysis of i-NOS protein expression and measurement of i-NOS activity were carried out in grafts harvested on Day 7, along with immunohistochemical and histopathological examinations. RESULTS: In the allograft group, both BUN and SCr levels increased markedly on Day 7, in parallel with a sharp increase in NOx. A band stained by anti-i-NOS antibody was detected at approximately 130 kDa, along with high levels of i-NOS activity and diffusely distributed i-NOS-positive cells (macrophages). Histologically, an acute rejection episode was confirmed (Grade 3 according to Banff classifications). In the AG group, reduced renal function and graft injury were significantly less severe than in the allograft group. CONCLUSIONS: In rat renal allograft acute rejection, markedly increased levels of serum NOx were observed, along with enhanced tissue i-NOS activity, together resulting in graft injury. AG administration suppressed the increase of serum NOx levels, with concomitant mitigation of tissue injury and renal function impairment.     

The effects of cyclic mechanical strain and tumor necrosis factor alpha on the response of cells of the meniscus

OBJECTIVES: Cells of the knee meniscus respond to changes in their biochemical and biomechanical environments with alterations in the biosynthesis of matrix constituents and inflammatory mediators. Tumor necrosis factor alpha (TNF-alpha) is a pro-inflammatory cytokine that is involved in the pathogenesis of both osteoarthritis and rheumatoid arthritis, but its influence on meniscal physiology or mechanobiology is not fully understood. The objectives of this study were to examine the hypothesis that cyclic mechanical strain of meniscal cells modulates the biosynthesis of matrix macromolecules and pro-inflammatory mediators, and to determine if this response is altered by TNF-alpha. METHODS: Cells were isolated from the inner two-thirds of porcine medial menisci and subjected to biaxial tensile strain of 5-15% at a frequency of 0.5Hz. The synthesis of proteoglycan, protein, nitric oxide (NO), and prostaglandin E(2) were determined. RESULTS: Cyclic tensile strain increased the production of nitric oxide through the upregulation of nitric oxide synthase 2 (NOS2) and also increased synthesis rates of prostaglandin E(2), proteoglycan, and total protein in a manner that depended on strain magnitude. TNF-alpha increased the production of NO and total protein, but inhibited proteoglycan synthesis rates. TNF-alpha prevented the mechanical stimulation of proteoglycan synthesis, and this effect was not dependent on NOS2. CONCLUSIONS: These findings indicate that pro-inflammatory cytokines can modulate the responses of meniscal cells to mechanical signals, suggesting that both biomechanical and inflammatory factors could contribute to the progression of joint disease as a consequence of altered loading of the meniscus.     

In vitro mechanical compression induces apoptosis and regulates cytokines release in hypertrophic scars

Hypertrophic scars resulting from severe burns are usually treated by continuous elastic compression. Although pressure therapy reaches success rates of 60-85% its mechanisms of action are still poorly understood. In this study, apoptosis induction and release of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) were evaluated in normal (n = 3) and hypertrophic (=7) scars from burns after in vitro mechanical compression. In the absence of compression (basal condition) apoptotic cells, scored using terminal deoxyribonucleotidyl transferase assay, were present after 24 hours in the derma of both normal scar (23 +/- 0.4% of total cell) and hypertrophic scar (11.3 +/- 1.4%). Mechanical compression (constant pressure of 35 mmHg for 24 hours) increased apoptotic cell percentage both in normal scar (29.5 +/- 0.4%) and hypertrophic scar (29 +/- 1.7%). IL-1beta released in the medium was undetectable in normal scar under basal conditions while in hypertrophic scar the IL-1beta concentration was 3.48 +/- 0.2 ng/g. Compression in hypertrophic scar-induced secretion of IL-1beta twofold higher compared to basal condition. (7.72 +/- 0.2 ng/g). TNF-alpha basal concentration measured in normal scar medium was 8.52 +/- 4.01 ng/g and compression did not altered TNF-alpha release (12.86 +/- 7.84 ng/g). TNF-alpha basal release was significantly higher in hypertrophic scar (14.74 +/- 1.42 ng/g) compared to normal scar samples and TNF-alpha secretion was diminished (3.52 +/- 0.97 ng/g) after compression. In conclusion, in our in vitro model, mechanical compression resembling the clinical use of elastocompression was able to strongly increase apoptosis in the hypertrophic scar derma as observed during granulation tissue regression in normal wound healing. Moreover, the observed modulation of IL-1beta and TNF-alpha release by mechanical loading could play a key role in hypertrophy regression induced by elastocompression.     

Ghrelin down-regulates proinflammatory cytokines in sepsis through activation of the vagus nerve

OBJECTIVE: To test the hypothesis that administration of ghrelin attenuates inflammatory responses in sepsis through vagal nerve stimulation. SUMMARY BACKGROUND DATA: Ghrelin has been demonstrated to possess multiple functions, including stimulation of the vagus nerve. Our recent study has shown that plasma levels of ghrelin were significantly reduced in sepsis; and ghrelin administration improved organ perfusion and function. However, it remained unknown whether ghrelin also decreases proinflammatory cytokines in sepsis and, if so, whether the down-regulatory effect of ghrelin is mediated by activation of the vagus nerve. METHODS: Male rats were subjected to sepsis by cecal ligation and puncture (CLP). At 5 hours after CLP, a bolus intravenous injection of 2 nmol ghrelin was followed by a continuous infusion of 12 nmol ghrelin via a primed 200-microL Alzet mini-pump for 15 hours. At 20 hours after CLP, plasma and peritoneal fluid levels of TNF-alpha and IL-6 were determined. The direct effect of ghrelin on cytokine production was studied using cultured normal rat Kupffer cells or peritoneal macrophages stimulated by lipopolysaccharide (LPS). In additional animals, vagotomy or sham vagotomy was performed in sham and septic animals immediately prior to ghrelin administration and cytokine levels were then measured. RESULTS: Ghrelin significantly reduced TNF-alpha and IL-6 levels in sepsis. In contrast, ghrelin did not inhibit TNF-alpha and IL-6 release from LPS-stimulated Kupffer cells or peritoneal macrophages. However, vagotomy, but not sham vagotomy, prevented ghrelin's down-regulatory effect on TNF-alpha and IL-6 production. CONCLUSIONS: Ghrelin down-regulates proinflammatory cytokines in sepsis through activation of the vagus nerve. Pharmacologic stimulation of the vagus nerve may offer a novel approach of anti-sepsis therapy.