Elaboration Of Proinflammatory Cytokines Research Articles

IGF-1 Deficiency Rescue and Intracellular Calcium Blockade Improves Survival and Corresponding Mechanisms in a Mouse Model of Acute Kidney Injury.

This study was undertaken to test two therapies for acute kidney injury (AKI) prevention, IGF-1, which is renal protective, and BTP-2, which is a calcium entry (SOCE) inhibitor. We utilized lipopolysaccharide (LPS) IP, as a systemic model of AKI and studied in five groups of animals. Three experiments showed that at 7 days: (1) LPS significantly reduced serum IGF-1 and intramuscular IGF-I in vivo gene therapy rescued this deficiency. (2) Next, at the 7-day time point, our combination therapy, compared to the untreated group, caused a significant increase in survival, which was noteworthy because all of the untreated animals died in 72 h. (3) The four pathways associated with inflammation, including (A) increase in cytosolic calcium, (B) elaboration of proinflammatory cytokines, (C) impairment of vascular integrity, and (D) cell injury, were adversely affected in renal tissue by LPS, using a sublethal dose of LPS. The expression of several genes was measured in each of the above pathways. The combined therapy of IGF-1 and BTP-2 caused a favorable gene expression response in all four pathways. Our current study was an AKI study, but these pathways are also involved in other types of severe inflammation, including sepsis, acute respiratory distress syndrome, and probably severe coronavirus infection.

Macrophage neuronal nitric oxide synthase (NOS1) controls the inflammatory response and foam cell formation in atherosclerosis

Vascular inflammation plays a decisive role in the formation of foam cells and in the pathophysiology of atherosclerosis. However, the underlying mechanisms of these processes are not clearly understood. Macrophages engulf oxidized low-density lipoproteins (OxLDLs) via a scavenger receptor (SR), an event that mediates the elaboration of proinflammatory cytokines to initiate necrotic core formation in atherogenic plaques. In this study, we demonstrate that Nitric oxide synthase 1 (NOS1)-derived nitric oxide (NO) promotes OxLDL uptake and enhances the release of proinflammatory cytokines by macrophages. Conversely, we show that NOS1 inhibition by N(G)-nitro-L-arginine methyl ester (L-NAME) suppresses OxLDL uptake and proinflammatory cytokine expression. Current studies indicate that NOS1 plays a crucial role in vascular inflammation and in the progression of atherosclerosis. Therefore, interference with NOS1 enzymatic activity should serve as an effective strategy to reduce foam cell formation and limit the extent of atherosclerotic plaque expansion.

The impact of alcohol use disorders on pulmonary immune cell inflammatory responses to Streptococcus pneumoniae.

Community-acquired pneumonia due to Streptococcus pneumoniae occurs commonly in alcohol use disorders (AUDs). Pneumonia in the AUD patient is associated with poorer outcomes, and specific therapies to mitigate disease severity in these patients do not exist. Numerous investigations have attributed increased severity of pneumonia in AUDs to aberrant function of the alveolar macrophage (AM), a lung immune cell critical in host defense initiation. No studies have examined the response of human AMs to S.pneumoniae in AUDs. We hypothesized that the inflammatory mediators released by AMs after S.pneumoniae stimulation would differ quantitatively in individuals with AUDs compared to non-AUD participants. We further postulated that AM inflammatory mediators would be diminished after exposure to the antioxidant, N-acetylcysteine (NAC). For comparison, responses of peripheral blood mononuclear cells (PBMCs) to pneumococcal protein were also examined. Otherwise healthy participants with AUDs and smoking-matched controls underwent bronchoalveolar lavage and peripheral blood sampling to obtain AMs and PBMCs, respectively. Freshly collected cells were cultured with increasing doses of heat-killed S.pneumoniae protein, with and without exposure to N-acetylcysteine. Cell culture supernatants were collected, and inflammatory mediators were measured, including interferon (IFN)-γ, interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. IFN-γ and IL-6 were significantly higher in unstimulated AM cell culture supernatants from subjects with AUDs. After stimulation with pneumococcal protein, a dose-response and time-dependent increase in pro-inflammatory cytokine production by both AMs and PBMCs was also observed; differences were not observed between AUD and non-AUD subjects. Addition of NAC to pneumococcal-stimulated AMs and PBMCs was generally associated with diminished cytokine production, with the exception of IL-1β that was elevated in AM culture supernatants from subjects with AUDs. Our observations suggest that AUDs contribute to basal alterations in AM pro-inflammatory cytokine elaboration, but did not support consistent differences in pneumococcal-stimulated AM or PBMC inflammatory mediator secretion that were referable to AUDs.

The Role of Carrageenan and Carboxymethylcellulose in the Development of Intestinal Inflammation.

Although the exact pathophysiology remains unknown, the development of inflammatory bowel disease (IBD) is influenced by the interplay between genetics, the immune system, and environmental factors such as diet. The commonly used food additives, carrageenan and carboxymethylcellulose (CMC), are used to develop intestinal inflammation in animal models. These food additives are excluded from current dietary approaches to induce disease remission in Crohn’s disease such as exclusive enteral nutrition (EEN) using a polymeric formula. By reviewing the existing scientific literature, this review aims to discuss the role that carrageenan and CMC may play in the development of IBD. Animal studies consistently report that carrageenan and CMC induce histopathological features that are typical of IBD while altering the microbiome, disrupting the intestinal epithelial barrier, inhibiting proteins that provide protection against microorganisms, and stimulating the elaboration of pro-inflammatory cytokines. Similar trials directly assessing the influence of carrageenan and CMC in humans are of course unethical to conduct, but recent studies of human epithelial cells and the human microbiome support the findings from animal studies. Carrageenan and CMC may trigger or magnify an inflammatory response in the human intestine but are unlikely to be identified as the sole environmental factor involved in the development of IBD or in disease recurrence after treatment. However, the widespread use of carrageenan and CMC in foods consumed by the pediatric population in a “Western” diet is on the rise alongside a corresponding increase in IBD incidence, and questions are being raised about the safety of frequent usage of these food additives. Therefore, further research is warranted to elucidate the role of carrageenan and CMC in intestinal inflammation, which may help identify novel nutritional strategies that hinder the development of the disease or prevent disease relapse post-EEN treatment.

Gender dimorphism in adipose tissue response to stress conditions

Obesity is a chronic low-grade inflammatory condition associated with the elaboration of proinflammatory cytokines and adipokines from adipose tissue. Gender dimorphism (in part due to sex hormones) has been identified after injury and hemorrhagic shock. We hypothesized that the sex hormones estrogen (E2) and testosterone (DHT) have disparate effects on inflammatory mediator production from adipose tissue under stress conditions. This was studied in an in vitro model. Mature adipocytes differentiated from adipose-derived stem cells were cocultured (2:1) with macrophages (RAW 264.7) and subjected to hypoxia/reoxygenation (H/R) and/or incubation with physiologic (10 μM) or stress (10 μM) concentrations of epinephrine (epi). Estrogen or DHT was added in a range of physiologic concentrations, and culture supernatants were obtained 12 hours after incubation, and tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and adiponectin levels were measured by enzyme-linked immunosorbent assay. Basal TNF-α and IL-6 release from cocultures was significantly increased in response to epi and/or H/R conditions. Estrogen decreased cytokine release to basal levels, whereas DHT had no effect. Of note, varying the concentration of epi had no effect on cytokine release. Basal levels of adiponectin release were significantly decreased in response to epi and/or H/R conditions. Estrogen exposure returned adiponectin levels to basal levels, whereas DHT had no effect. The inverse of this relationship was observed in regard to the sex hormones effect on leptin release. Estrogen returned leptin release to basal levels, whereas DHT had no effect. Stress levels of epi and H/R increased proinflammatory cytokine production and decreased adiponectin levels in adipocyte cocultures. Estrogen at physiologic concentrations decreased TNF-α, IL-6, and preserved adiponectin levels following epi and/or H/R conditions. There was no effect of DHT on mitigating the proinflammatory response. Our results suggest a gender dimorphism in adipose tissue under stress conditions that may explain the conflicting data in the literature.

CHANGES IN THE LEVELS OF ANGIOTENSIN II, ALDOSTERONE, AND FIBROBLAST GROWTH FACTOR IN PATIENTS WITH RHEUMATOID ARTHRITIS IN RELATION TO CLINICAL FEATURES

Angiotensin II, aldosterone, and fibroblast growth factor (FGF) stimulate neoangiogenesis, fibroblast proliferation, and elaboration of proinflammatory cytokines, which in turn contributes to increased pannus mass and the development of joint tissue destruction in rheumatoid arthritis (RA). Objective: to establish the specific features of changes in the blood levels of angiotensin II, aldosterone, and FGF in patients with RA in relation to the duration and severity of the disease. Subjects and methods. Examinations were made in 194 patients diagnosed with RA without comorbidity; the patients’ mean age was 47.7±10.2 years; the disease duration was 3.82±3.43 years. DAS28 scores for RA were calculated based on C-reactive protein levels. An enzyme immunoassay was used to determine the serum levels of anti-cyclic citrullinated peptide antibodies (ACCPA), angiotensin II, aldosterone, and FGF. Results and discussion. All the examinees were ascertained to have increases in the concentration of angiotensin II and aldosterone in blood by twice and in that of FGF by 2.5 times compared to the controls (p 5 years and the concentrations of aldosterone and FGF in patients with long-term RA were twice as high as in those with early RA. In patients with high RA activity, the blood level of angiotensin II was 1.5-fold higher than in those with low and moderate disease activity (p < 0.05). In patients with a high blood ACCPA level, the concentrations of angiotensin II, aldosterone, and FGF were 20, 30, and 25%, respectively, higher than in those with low ACCPA levels. The correlation of DAS28 with blood angiotensin II levels increased with enhanced RA activity. The high aldosterone and FGF values in RA patients are associated with the progression of joint radiographic changes.

Diminished reovirus capsid stability alters disease pathogenesis and littermate transmission.

Reovirus is a nonenveloped mammalian virus that provides a useful model system for studies of viral infections in the young. Following internalization into host cells, the outermost capsid of reovirus virions is removed by endosomal cathepsin proteases. Determinants of capsid disassembly kinetics reside in the viral σ3 protein. However, the contribution of capsid stability to reovirus-induced disease is unknown. In this study, we found that mice inoculated intramuscularly with a serotype 3 reovirus containing σ3-Y354H, a mutation that reduces viral capsid stability, succumbed at a higher rate than those infected with wild-type virus. At early times after inoculation, σ3-Y354H virus reached higher titers than wild-type virus at several sites within the host. Animals inoculated perorally with a serotype 1 reassortant reovirus containing σ3-Y354H developed exaggerated myocarditis accompanied by elaboration of pro-inflammatory cytokines. Surprisingly, unchallenged littermates of mice infected with σ3-Y354H virus displayed higher titers in the intestine, heart, and brain than littermates of mice inoculated with wild-type virus. Together, these findings suggest that diminished capsid stability enhances reovirus replication, dissemination, lethality, and host-to-host spread, establishing a new virulence determinant for nonenveloped viruses.

Parthenolide from Parthenium integrifolium reduces tumor burden and alleviate cachexia symptoms in the murine CT-26 model of colorectal carcinoma

Excessive elaboration of proinflammatory cytokines are involved in cachexia-related hypercatabolism. Parthenolide, as a potential anti-inflammatory active agent, could effectively inhibit nuclear factor-kappa B, and has the potential for the treatment of cancer cachexia. In this study, the cancer cachexia model was established by subcutaneous transplantation CT26 tumor fragment. Parthenolide or placebo was intraperitoneally given daily from the next day. Parthenolide treatment could effectively preserve the body weight, improve the mass of gastrocnemius and tibialis anterior muscles, and alleviate tumor burden. Sizes of muscle fibers and myosin heavy chain were also increasing. The serum proinflammatory cytokine TNF-α level was lower than placebo treatment mice measure by ELISA. To investigate the possible mechanism, MuRF1 and Fbx32 was subjected to Western blot analysis and expression of MURF1 was inhibited in gastrocnemius muscle. Collectively, parthenolide treatment could effectively alleviate tumor burden of cachexia, preserve the body weight and improve skeletal muscle characteristics.

Abstract 221: Chronic Alterations of the Tissue Dendritic Cell and Macrophage Network Underlies the Th1 Response in the Failing Heart

Little is known about changes in the immune cell network that underlie pro-inflammatory cytokine elaboration in chronic heart failure (HF). Dendritic cells (DCs) and macrophages are antigen-presenting cells that play a central role in inflammation and immune tolerance. We investigated the pattern of infiltrating cardiac DCs and macrophages in chronic post-ischemic HF. Myocardial infarction (MI) was induced by left coronary ligation in male C57BL/6 mice. Pathological remodeling and HF were confirmed by hemodynamics, gravimetry, and echocardiography at 8 weeks post-MI. Sham-operated mice served as controls. At 8 weeks, cardiac infiltrating immune cells were isolated by collagenase digestion followed by density gradient centrifugation. Trypan blue-negative viable cells were quantified using flow cytometry. DCs were characterized using specific markers for classical (cDC) (CD11C+B220-), plasmacytoid (pDC) (CD11C+B220+), and immunogenic (CD11c+B220+CD86hi) and tolerogenic (CD11c+B220+CD86low) DCs. Macrophages were classified as activated (CD11b+F480+), pro- or anti-inflammatory (CD11b+F480+Gr1hi or low), and M1 (CD11b+F480+CD206-) or M2 (CD11b+F480+CD206+). Significant increases in cDCs (1.4 fold; p=0.016) and pDCs (4.3 fold; p=0.0016) were observed in failing myocardium. Surface expression of the maturation marker CD86 was increased 8.6 fold (p=0.009), whereas immature DCs exhibited a robust 24.4 fold (p=0.0005) increase. Activated macrophages were also significantly elevated in the failing heart as compared with sham-operated hearts (19.2 ± 1.9 vs 10.9 ± 2.9%; p=0.033), with marked infiltration of pro-inflammatory and M1 macrophages (6.2 ± 0.6 vs 3.8 ± 0.7%; p=0.019). In contrast, levels of anti-inflammatory and M2 macrophages were unchanged. We conclude that in chronic HF, there is marked upregulation of cDC and pDC subsets and pro-inflammatory/M1 macrophages that alter immune homeostasis, contribute to the recruitment and activation of immune cells, and underlie the chronic Th1 response in failing myocardium that promotes pathological remodeling. This suggests that targeting or altering immune cell subsets in the failing heart, rather than specific cytokines, may be a better approach to modulating inflammation in HF.

A review of obesity and orthopaedic surgery: The critical issues

Obesity is a growing concern in the health community because of the morbidities associated with it. There is a higher occurrence of many orthopaedic conditions among obese individuals than their non-obese counter parts. Obesity also worsens the progression of many of these orthopaedic conditions. Studies have shown that obesity may have negative impact on bone metabolism and may be implicated in the pathophysiology of some orthopaedic conditions like osteoporosis, fractures, osteoarthritis and many soft tissue ailments by both reduction in bone mass and elaboration of proinflammatory cytokines. These contribute to preponderance of musculoskeletal co-morbidities among obese patients. Critical peri-operative issues which include increased cardiopulmonary risks, issues of special equipment, instrumentation, surgical approach, patients' positioning and adjustments in medication should be acknowledged and meticulously addressed in operative management of orthopaedic conditions in obese patients. Surgeries in obese patients are fraught with operative challenges and post-operative complications than in the non-obese and a good knowledge of the critical issues in surgical management of obese patients is necessary to facilitate decision making as well as rendering of effective and efficient orthopaedic care.

Maternal Schistosomiasis Japonica Is Associated with Maternal, Placental, and Fetal Inflammation

Schistosomes infect ∼40 million women of childbearing age and result in the elaboration of proinflammatory cytokines that have been implicated in fetal growth restriction. In murine models and two observational studies in humans, schistosome infection during pregnancy was associated with reduced birth weight, although a recent treatment trial in Schistosoma mansoni did not detect this association. We conducted an observational study among 99 pregnant women living in an area of Schistosoma japonicum endemicity in the Philippines. We enrolled women at 32 weeks gestation and measured S. japonicum and geohelminth infection intensity. We collected maternal peripheral blood at 32 weeks gestation and placental and cord blood at delivery to assess inflammatory status. At delivery, we collected a placental-tissue sample and measured birth weight. In multivariate models adjusted for geohelminths, maternal schistosomiasis was associated with increased levels of inflammatory cytokines in maternal peripheral (tumor necrosis factor alpha [TNF-α] and interleukin 10 [IL-10]), placental (TNF-α, IL-6, TNF-α receptor II [RII], and IL-1β), and cord (IL-1β and TNF-α RII) blood, as well as acute subchorionitis and increased TNF-α production by syncytiotrophoblasts assessed by immunohistochemistry (all P < 0.05). After adjusting for confounders, placental IL-1β, and TNF-α production by syncytiotrophoblasts was independently associated with decreased birth weight (both P < 0.05). Our data indicate that maternal schistosomiasis results in a proinflammatory signature that is detectable in maternal, placental, and fetal compartments, and a subset of these responses are associated with decreased birth weight. This potential mechanistic link between maternal schistosomiasis and poor birth outcomes will contribute to the debate regarding treatment of maternal schistosome infections.

The Prostaglandin E2 E-Prostanoid 4 Receptor Exerts Anti-Inflammatory Effects in Brain Innate Immunity

Peripheral inflammation leads to immune responses in brain characterized by microglial activation, elaboration of proinflammatory cytokines and reactive oxygen species, and secondary neuronal injury. The inducible cyclooxygenase (COX), COX-2, mediates a significant component of this response in brain via downstream proinflammatory PG signaling. In this study, we investigated the function of the PGE2 E-prostanoid (EP) 4 receptor in the CNS innate immune response to the bacterial endotoxin LPS. We report that PGE2 EP4 signaling mediates an anti-inflammatory effect in brain by blocking LPS-induced proinflammatory gene expression in mice. This was associated in cultured murine microglial cells with decreased Akt and I-kappaB kinase phosphorylation and decreased nuclear translocation of p65 and p50 NF-kappaB subunits. In vivo, conditional deletion of EP4 in macrophages and microglia increased lipid peroxidation and proinflammatory gene expression in brain and in isolated adult microglia following peripheral LPS administration. Conversely, EP4 selective agonist decreased LPS-induced proinflammatory gene expression in hippocampus and in isolated adult microglia. In plasma, EP4 agonist significantly reduced levels of proinflammatory cytokines and chemokines, indicating that peripheral EP4 activation protects the brain from systemic inflammation. The innate immune response is an important component of disease progression in a number of neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In addition, recent studies demonstrated adverse vascular effects with chronic administration of COX-2 inhibitors, indicating that specific PG signaling pathways may be protective in vascular function. This study supports an analogous and beneficial effect of PGE2 EP4 receptor signaling in suppressing brain inflammation.

Sepsis-induced myopathy

Sepsis is a major cause of morbidity and mortality in critically ill patients, and despite advances in management, mortality remains high. In survivors, sepsis increases the risk for the development of persistent acquired weakness syndromes affecting both the respiratory muscles and the limb muscles. This acquired weakness results in prolonged duration of mechanical ventilation, difficulty weaning, functional impairment, exercise limitation, and poor health-related quality of life. Abundant evidence indicates that sepsis induces a myopathy characterized by reductions in muscle force-generating capacity, atrophy (loss of muscle mass), and altered bioenergetics. Sepsis elicits derangements at multiple subcellular sites involved in excitation contraction coupling, such as decreasing membrane excitability, injuring sarcolemmal membranes, altering calcium homeostasis due to effects on the sarcoplasmic reticulum, and disrupting contractile protein interactions. Muscle wasting occurs later and results from increased proteolytic degradation as well as decreased protein synthesis. In addition, sepsis produces marked abnormalities in muscle mitochondrial functional capacity and when severe, these alterations correlate with increased death. The mechanisms leading to sepsis-induced changes in skeletal muscle are linked to excessive localized elaboration of proinflammatory cytokines, marked increases in free-radical generation, and activation of proteolytic pathways that are upstream of the proteasome including caspase and calpain. Emerging data suggest that targeted inhibition of these pathways may alter the evolution and progression of sepsis-induced myopathy and potentially reduce the occurrence of sepsis-mediated acquired weakness syndromes.

Immunoregulatory peptides from salivary glands of the horsefly, Tabanus pleskei

Horseflies are economically important blood-feeding arthropods and vectors for several pathogenic microorganisms. Horseflies rely heavily on pharmacological propriety of their saliva to get blood meal and suppress immune reactions of hosts. Few reports cover immune suppressants from horsefly salivary glands. Three immunoregulatory peptides named immunoregulin TP1-3 have been identified and characterized from salivary glands of the horsefly Tabanus pleskei (Diptera, Tabanidae). Immunoregulin TP1 could inhibit the secretion of interferon-gamma (IFN-gamma), monocyte chemoattractant protein (MCP-1) and increase the secretion of interleukin-10 (IL-10) induced by lipopolysaccharide (LPS) in mouse splenocytes. IL-10 is a suppressor cytokine of T-cell proliferation and cytokine responses. IL-10 can inhibit the elaboration of pro-inflammatory cytokines. In the current studies, Immunoregulin TP1 inhibited the IFN-gamma and MCP-1 secretion possibly by upregulating the IL-10 production, and finally might facilitate the blood-feeding of this horsefly. The current works will help understand the molecular mechanisms of the ectoparasite-host relationship.

Isolation and functional characterization of T cells from human sputum.

T cells play a central role in the control of inflammation in the bronchial mucosa through the elaboration of proinflammatory cytokines. This study describes a method for the isolation and cloning of T cells from sputum of adult subjects. In sputum, T cells were of a minor population (< 2% of total cells), and not all expressed activation markers for CD29 (very late antigen-1 (VLA-1)), IL-2R and HLA-DR. When cultured in the presence of rIL-2 for 7 days and then cloned by limiting dilution, the ratios of CD4+ and CD8+ T cell clones (TCC) generated reflected those of CD4+ and CD8+ T cells found in sputum. CD4+ TCC and primary CD4+ T cell populations produced a range of proinflammatory cytokines when stimulated with immobilized anti-CD3 MoAb. Analysis of mRNA messages by reverse transcriptase-polymerase chain reaction (RT-PCR) and Southern blot showed good correlation with the production of cytokine in culture supernatants. A correlation existed between the pattern of cell infiltrate in sputum and the cytokine profile.

An immunoregulatory peptide from salivary glands of the horsefly, Hybomitra atriperoides

Horseflies are economically important blood-feeding arthropods and also a nuisance for humans, and vectors for filariasis. They rely heavily on the pharmacological propriety of their saliva to get blood meal and suppress immune reactions of hosts. Little information is available on horsefly immune suppressants. By high-performance liquid chromatography (HPLC) purification coupling with pharmacological testing, an immunoregulatory peptide named immunoregulin HA has been identified and characterized from salivary glands of the horsefly of Hybomitra atriperoides (Diptera, Tabanidae). Immunoregulin HA could inhibit the secretion of interferon-gamma (IFN-gamma) and monocyte chemoattractant protein (MCP-1) and increase the secretion of interleukin-10 (IL-10) induced by lipopolysaccharide (LPS) in rat splenocytes. IL-10 is a suppressor cytokine of T-cell proliferative and cytokine responses. IL-10 can inhibit the elaboration of pro-inflammatory cytokines. Immunoregulin HA possibly unregulated the IL-10 production to inhibit IFN-gamma and MCP-1 secretion in the current experiments. This immunosuppression may facilitate the blood feeding of this horsefly. The current works will facilitate to understand the molecular mechanisms of the ectoparasite-host relationship.

Regulation of hepatic NF‐κB activation during reperfusion after normothermic and hypothermic ischemia

Hepatic ischemia/reperfusion (I/R) injury may occur as a result of liver resectional surgery or transplantation. Throughout the history of liver surgery, hypothermic techniques have shown some benefit in the prevention of ischemic injury. We have previously shown that hypothermia attenuates the inflammatory response induced by ischemia/reperfusion. Because the transcription factor, NF-κB, is known to be a primary regulator of inflammatory gene expression, we sought to determine if hypothermia affected the activation of this transcription factor. Male C57BL/6 mice were subjected to 90 minutes of partial hepatic ischemia followed by up to 8 hours of reperfusion. One group of mice had their body temperature maintained at 36.5 ± 0.2 °C (normothermic) throughout the surgical procedure and recovery period. In the other group of mice (hypothermic), body temperature was uncontrolled during the period of liver ischemia and was quickly returned to normal upon reperfusion. In this latter group, mean rectal temperature fell to 23.1 ± 0.5 °C by the end of the ischemic period. Hypothermic mice were significantly protected from hepatic I/R injury, as determined by serum ALT. Hypothermia resulted in reduced serum levels of the proinflammatory chemokine, TNFα. However, there was increased NF-κB activation in hypothermic mice compared to normothermic mice. IKK kinase activity was also increased in livers of hypothermic mice compared to normothermic mice. Immunofluorescence staining of NF-κB p65 in liver sections indicated that the increased activation in hypothermic mice occurred widely in hepatocytes. We conclude that NF-κB activation in hepatocytes in hypothermic mice is hepatoprotective and that in normothermic mice, NF-κB activity likely occurs in Kupffer cells leading to the elaboration of proinflammatory cytokines.

This Month in Gastroenterology

This Month in Gastroenterology

HO-1 Upregulation Suppresses Type 1 IFN Pathway in Hepatic Ischemia/Reperfusion Injury

Upregulation of heme oxygenase (HO)-1, a heat shock protein 32, protects against hepatic ischemia/reperfusion (I/R) injury. Activation of “innate” toll-like receptor (TLR) 4 system triggers the I/R injury cascade. This study explores cytoprotective functions of HO-1 overexpression following exogenous administration of cobalt protoporphyrin (CoPP), and its relationship with the TLR4 pathway in a model of mouse partial hepatic warm I/R injury. CoPP treatment markedly improved hepatic function and histology, and suppressed pro-inflammatory cytokine elaboration profile, as compared with untreated controls. Although administration of CoPP did not affect intrahepatic TLR4, it downregulated IFN-inducible protein 10 (IP-10) expression. As IP-10 is the major product of type-1 IFN pathway downstream of TLR4, we then infused recombinant IFN-β (rIFN-β) directly into mouse livers. Interestingly, infusion of rIFN-β upregulated hepatic IP-10 expression. In contrast, adjunctive CoPP treatment decreased IP-10 levels in mouse livers infused with rIFN-β. Thus, CoPP-induced HO-1 upregulation suppresses type-1 IFN pathway downstream of TLR4 system in hepatic warm I/R injury model.

AEROSOL-ADMINISTERED α-TOCOPHEROL ATTENUATES LUNG INFLAMMATION IN RATS GIVEN LIPOPOLYSACCHARIDE INTRATRACHEALLY

Intrapulmonary administration of bacterial lipopolysaccharide (LPS) induces a well-characterized lung inflammatory response involving alveolar macrophage activation, proinflammatory cytokine elaboration, and neutrophil influx. Vitamin E, a lipophilic antioxidant consisting of a family that includes tocopherols and tocotrienols, has previously been shown to have a variety of anti-inflammatory effects, raising interest in its possible uses in disease prevention or therapy. Because aerosol delivery is a specific and rapid way to administer agents to the lungs, the authors undertook to determine whether inhaled vitamin E aerosols would have an anti-inflammatory effect in the lungs. Using a rat model of acute lung inflammation caused by intratracheally administered LPS (10 μg Pseudomonas aeruginosa LPS), the authors examined the effect of aerosol-administered vitamin E, in this case α-tocopherol, on several indices of lung inflammation which are increased by LPS treatment. It was found that inhaled α-tocopherol aerosol, but not inhaled α-tocopherol acetate aerosol, decreased tumor necrosis factor alpha (TNFα) and cytokine-induced neutrophil chemoattractant-1 (CINC-1) mRNA levels in lung tissue, TNFα and CINC-1 immunoreactive protein levels in lung lavage, and the number of neutrophils recoverable by lung lavage from rats given LPS intratracheally. These results contribute to the increasing body of work describing immunomodulatory functions of α-tocopherol, and support the idea that direct aerosol administration of α-tocopherol may play a beneficial role in strategies to control inflammatory lung illnesses.