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Exposure to nicotine is probably a major cause of inflammatory diseases among non-smokers.

This article assesses the hypothesis that most inflammatory diseases are conditioned responses caused by the psychoactive action of nicotine. Even in very 'light' passive smokers, the repeated nicotinic stimulation of the reward system can produce, through classical and subsequent operant conditioning, unconscious addiction to most relevant perceptions occurring simultaneously, including the artificial, non-localised sensation of pain or sickness caused by the action of nicotine on the nociceptive 'cholinergic anti-inflammatory pathway'. During nicotine abstinence and especially under stress, the brain previously addicted to this pain is compelled to reproduce it by the only method available without nicotine: causing lesions or cellular stress in one's organism, for example, by triggering intense inflammations. The author's observations and two independent studies have confirmed that nicotine withdrawal causes inflammatory crises. Furthermore, there is evidence that severe inflammations can be triggered even by almost unnoticeable exposures to nicotine, for example, by staying several minutes outdoors at a few metres from smokers. This has been clearly observed by one patient and can be deduced from theoretical considerations (sensitivity of neural pathways and cumulativeness of conditioning processes) and an animal experimental reference, and is confirmed by the fact that most inflammatory diseases affect similarly all non-smokers regardless of their apparent exposure to nicotine, despite the proven relation between nicotine withdrawal and inflammation. This sensitivity implies that the outdoors atmosphere of most densely populated urban areas represents now a serious health hazard, probably requiring the prohibition of all smokable forms of nicotine. The usual anti-smoking measures focused on closed spaces are inefficient against this danger.

Acetylcholine↗

A scarlet pimpernel for the resolution of inflammation? The role of supra-therapeutic doses of cobalamin, in the treatment of systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, and septic or traumatic shock.

Cobalamin carrier proteins,the Transcobalamins (TCS), are elevated during trauma, infections and chronic inflammatory conditions. This remains un-explained. It is proposed that such TC elevations signal a need for cobalamin central to the resolution of inflammation. Thus Cobalamin may regulate the transcription factor, NFkappaB, activation or suppression of which determines the inflammatory response and its resolution. Such regulation may involve at least 5 separate mechanisms: (i) hormone-like regulation of TNFalpha, through reduction of excess NO by cobalamin, as well as through the selective inhibition, in tandem with glutathione, of inducible nitric oxide synthase; (ii) quenching of nitric oxide radicals and reactive oxygen species, enhanced by cobalamin's glutathione sparing effect; (iii) the promotion of acetylcholine synthesis, central to the neuro-immune cholinergic anti-inflammatory pathway; (iv) the promotion of oxidative phosphorylation; (v) and a bacteriostatic role of the TCS released by neutrophil secondary granules during phagocytosis, which also appears to modulate the inflammatory response. TC elevations are dependent on NFkappaB activation, through crosstalk between NFkappaB and Sp1, another member of the helix-loop-helix protein family, which directly mediates transcription of the TCII gene. Sp1 also has binding sites on the TNFalpha and EGF gene promoters. NFkappaB may thus ensure sufficient cobalamin to determine its own eventual suppression. Cobalamin's established regulation of EGF may additionally preserve normal function of macrophages and the coagulation cascade in wound healing. By regulating NFkappaB, Cobalamin may also be the as yet unidentified mediator needed to potentiate the anti-inflammatory action of eicosanoids derived from omega-3 essential fatty acids. Moreover, animal and human clinical data suggests that high dose cobalamin may prove a promising approach to SIRS/sepsis/septic and traumatic shock.

Acetylcholine↗

Drug insight: Immunomodulatory effects of statins--potential benefits for renal patients?

Statins inhibit 3-hydroxyl-3-methylglutaryl coenzyme A reductase, an enzyme crucial to cholesterol synthesis. Drugs of this class reduce the risk of coronary heart disease and stroke, in large part through lipid modulation. Emerging evidence indicates that statins have additional modes of action. These actions, which encompass modification of endothelial function, plaque stability, thrombus formation and inflammatory pathways, are widely referred to as 'pleiotropic effects'. These pleiotropic effects indicate that the therapeutic potential of statins might extend beyond cholesterol lowering and cardiovascular disease to other inflammatory disorders or conditions such as transplantation, multiple sclerosis, rheumatoid arthritis and chronic kidney disease. Experimental and clinical data provide evidence to support these broader applications of statins; however, more large-scale trials are needed to clarify the therapeutic benefit.

Animals↗

Inflammation in Alzheimer disease: driving force, bystander or beneficial response?

Alzheimer disease is a progressive dementia with unknown etiology that affects a growing number of the aging population. Increased expression of inflammatory mediators in postmortem brains of people with Alzheimer disease has been reported, and epidemiological studies link the use of anti-inflammatory drugs with reduced risk for the disorder. On the initial basis of this kind of evidence, inflammation has been proposed as a possible cause or driving force of Alzheimer disease. If true, this could have important implications for the development of new treatments. Alternatively, inflammation could simply be a byproduct of the disease process and may not substantially alter its course. Or components of the inflammatory response might even be beneficial and slow the disease. To address these possibilities, we need to determine whether inflammation in Alzheimer disease is an early event, whether it is genetically linked with the disease and whether manipulation of inflammatory pathways changes the course of the pathology. Although there is still little evidence that inflammation triggers or promotes Alzheimer disease, increasing evidence from mouse models suggests that certain inflammatory mediators are potent drivers of the disease. Related factors, on the other hand, elicit beneficial responses and can reduce disease.

Alzheimer Disease↗

Fluvastatin in the therapy of acute coronary syndrome: Rationale and design of a multicenter, randomized, double-blind, placebo-controlled trial (The FACS Trial)[ISRCTN81331696].

BACKGROUND: Activation of inflammatory pathways plays an important contributory role in coronary plaque instability and subsequent rupture, which can lead to the development of acute coronary syndrome (ACS). Elevated levels of serum inflammatory markers such as C-reactive protein (CRP) represent independent risk factors for further cardiovascular events. Recent evidence indicates that in addition to lowering cholesterol levels, statins also decrease levels of inflammatory markers. Previous controlled clinical trials reporting the positive effects of statins in participants with ACS were designed for very early secondary prevention. To our knowledge, no controlled trials have evaluated the potential benefits of statin therapy, beginning immediately at the time of hospital admission. A previous pilot study performed by our group focused on early initiation of cerivastatin therapy. We demonstrated a highly significant reduction in levels of inflammatory markers (CRP and interleukin-6). Based on these preliminary findings, we are conducting a clinical trial to evaluate the efficacy of another statin, fluvastatin, as an early intervention in patients with ACS. METHODS: The FACS-trial (Fluvastatin in the therapy of Acute Coronary Syndrome) is a multicenter, randomized, double-blind, placebo-controlled study evaluating the effects of fluvastatin therapy initiated at the time of hospital admission. The study will enroll 1,000 participants admitted to hospital for ACS (both with and without ST elevation). The primary endpoint for the study is the influence of fluvastatin therapy on levels of inflammatory markers (CRP and interleukin-6) and on pregnancy associated plasma protein A (PAPP-A). A combined secondary endpoint is 30-day and one-year occurrence of death, nonfatal myocardial infarction, recurrent symptomatic ischemia, urgent revascularization, and cardiac arrest. CONCLUSION: The primary objective of the FACS trial is to demonstrate that statin therapy, when started immediately after hospital admission for ACS, results in reduction of inflammation and improvement of prognosis. This study may contribute to new knowledge regarding therapeutic strategies for patients suffering from ACS and may offer additional clinical indications for the use of statins.

Journal Article↗

The effect of anti-inflammatory properties of mycophenolate mofetil on the development of lung reperfusion injury.

BACKGROUND: Lung ischemia-reperfusion injury (LIRI) is associated with an increased incidence of both primary graft failure and obliterative bronchiolitis. The immunosuppressant mycophenolate mofetil (MMF) has recently been shown to attenuate inflammatory injury in acute ischemia-reperfusion models via a mechanism that is presently unclear. These experiments studied the effects of MMF in a warm, in situ LIRI model, focusing on transcriptional regulation of pro-inflammatory mediators. METHODS: Left lungs of rats were rendered ischemic for 90 minutes and reperfused for up to 4 hours. Treated animals received 10 mg/kg of intravenous MMF at 2 hours before ischemia. Left lung injury was quantitated by myeloperoxidase (MPO) content, permeability indices and bronchoalveolar lavage (BAL) inflammatory cell counts. Lungs were analyzed by electrophoretic mobility shift assay (EMSA) for transcription factor transactivation and by enzyme-linked immunoassay for BAL chemokine protein content. RESULTS: MMF significantly reduced lung vascular permeability indices, MPO content and alveolar leukocyte counts at 4 hours of reperfusion. There was significant attenuation of activator protein 1 (AP-1) and early growth response 1 (EGR-1) transactivation, whereas nuclear factor-kappaB (NF-kappaB) was unaffected. Reductions in bronchoalveolar lavage monocyte chemoattractant protein 1 (MCP-1) and cytokine-induced neutrophil chemoattractant (CINC) protein content were found at 4 hours of reperfusion. CONCLUSIONS: MMF limits lung ischemia-reperfusion-induced increases in vascular permeability and inflammatory cell sequestration in lung parenchyma and alveolar spaces. The protection is mediated at the transcriptional level via an attenuation of early EGR-1 and AP-1 transactivation, which was found to be associated with reduced late MCP-1 and CINC protein secretion. The use of MMF in concert with an agent that affects NF-kappaB activation may provide even further protection against lung reperfusion injury as multiple inflammatory pathways are inhibited.

Animals↗

Immunomodulatory Effects of Omega-3 Fatty Acids: Mechanistic Insights and Health Implications.

Omega-3 fatty acids play a significant role in immunomodulation, with nutrigenomic approaches highlighting their impact on gene expression related to immune responses. Research indicates that omega-3 fatty acids can modulate inflammatory pathways, potentially reducing chronic inflammation and enhancing immune function. This review discusses the intersection of nutrigenomics and nutriepigenomics, focusing on how omega-3 fatty acids influence gene expression, immune function, and overall health. The immune system is a complex network responsible for defending the body against pathogens and maintaining internal balance. Comprised of innate and adaptive immunity, the system involves various cells, tissues, and organs working together to combat infections and prevent diseases. Omega-3 polyunsaturated fatty acids (PUFAs), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), play a significant role in modulating the immune system. These fatty acids influence immune cell function, membrane fluidity, and signaling processes, enhancing immune responses and reducing inflammation. Furthermore, EPA and DHA affect several signaling pathways, reducing the expression of proinflammatory cytokines and inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation, a critical transcription factor in the inflammatory response. Additionally, they activate PPAR-γ, further diminishing inflammatory gene expression. As precursors to specialized proresolving lipid mediators, EPA and DHA help shift the lipid mediator profile from proinflammatory to antiinflammatory derivatives, thus aiding in the resolution of inflammation.

Humans↗

Genetics of multiple sclerosis: determinants of autoimmunity and neurodegeneration.

Since the first description of multiple sclerosis (MS) as an inheritable disease by Eichhorst [1] accumulating epidemiological observations support a genetic hypothesis. Population, family and twin studies have revealed that Mendelian transmission of a single susceptibility gene would not be compatible with the observed patterns of inheritance. Like most other common diseases, MS is a complex trait, defined by several genes, each probably exerting a relatively small effect. Complex interactions among susceptibility genes and the environment are believed to contribute to a predisposition to dysregulation of inflammatory pathways, demyelination and tissue degeneration in the central nervous system (CNS). Natural history and pathological studies, however, define that MS represents a spectrum rather than a single entity of inflammatory demyelination. Despite a growing need for identifying molecular markers of biological subtypes of MS, only limited information is available for genotype-phenotype correlations. Four full genome scans using polymorphic microsatellite markers in nuclear and multiplex MS families indicated several chromosomal regions of susceptibility. With the recently discovered, highly abundant single nucleotide polymorphisms (SNPs) and family-based association methods, the means are now available to confine these relatively large regions of interest to candidate genes and susceptibility alleles. The currently available SNP maps favor indirect association studies based on linkage disequilibrium between marker and disease alleles. Here, we review available genetic data in MS, and introduce an additional strategy which correlate genetic markers with major biological components of the disease such as autoimmunity and neurodegeneration. This approach may yield important insights with utility in clinical practice.

Autoimmunity↗

Transgenic activation of the kallikrein-kinin system inhibits intramyocardial inflammation, endothelial dysfunction and oxidative stress in experimental diabetic cardiomyopathy.

The mechanisms contributing to diabetic cardiomyopathy, as well as the protective pathways of the kallikrein-kinin-system (KKS), are incompletely understood. In a kallikrein-overexpressing rat model of streptozotocin (STZ)-induced diabetic cardiomyopathy, we investigated the involvement of inflammatory pathways, endothelial dysfunction, and oxidative stress. Six weeks after STZ injection, impairment of left ventricular (LV) function parameters measured by a Millar-tip catheter (peak LV systolic pressure; dP/dtmax; dP/dtmin) was accompanied by a significant increment of ICAM-1 and VCAM-1 (CAMs) expression, as well as of beta2-leukocyte-integrins+ (CD18+, CD11a+, CD11b+) and cytokine (TNF-alpha and IL-1beta)-expressing infiltrates in male Sprague-Dawley (SD-STZ) rats compared with normoglycemic littermates. Furthermore, SD-STZ rats demonstrated a significant impairment of endothelium-dependent relaxation evoked by acetylcholine and significantly increased plasma TBARS (plasma thiobarbituric acid reactive substances) levels as a measure of oxidative stress. These diabetic cardiomyopathy-associated alterations were significantly attenuated (P<0.05) in diabetic transgenic rats expressing the human kallikrein 1 (hKLK1) gene with STZ-induced diabetes. CAMs expression, beta2-leukocyte-integrins+, and cytokine-expressing infiltrates correlated significantly with all evaluated LV function parameters. The multiple protective effects of the KKS in experimental diabetic cardiomyopathy comprise the inhibition of intramyocardial inflammation (CAMs expression, beta2-leukocyte-integrins+ infiltration and cytokine expression), an improvement of endothelium-dependent relaxation and the attenuation of oxidative stress. These insights might have therapeutic implications also for human diabetic cardiomyopathy.

Acetylcholine↗

New insights into the biology of the acute phase response.

Innate or natural immunity is a highly conserved defense mechanism against infection found in all multicellular organisms. The acute phase response is the set of immediate inflammatory responses initiated by pattern recognition molecules. These germ cell-encoded proteins recognize microbial pathogens based on shared molecular structures and induce host responses that localize the spread of infection and enhance systemic resistance to infection. Innate immunity also influences the initiation and type of adaptive immune response by regulating T cell costimulatory activity and antigen presentation by antigen presenting cells and by influencing mediator production, which affects lymphocyte function and trafficking. Acute phase protein concentrations rapidly increase after infection, and their production is controlled primarily by IL-6- and IL-1-type cytokines. The acute phase proteins provide enhanced protection against microorganisms and modify inflammatory responses by effects on cell trafficking and mediator release. For example, serum amyloid A has potent leukocyte activating functions including induction of chemotaxis, enhancement of leukocyte adhesion to endothelial cells, and increased phagocytosis. The constellation of inflammatory responses seen after endotoxin administration to humans represents an in vivo model of the acute phase response. Studies with inflammatory modifying agents, such as soluble dimeric TNF receptor and IL-10, show that these responses are not dependent on a single mediator but result from multiple overlapping inflammatory pathways. Understanding the factors that initiate and alter the magnitude and duration of the acute phase response represents an important step in the development of new therapies for infectious and inflammatory diseases.

Acute-Phase Proteins↗

Activation of phospholipase A2 is associated with generation of placental lipid signals and fetal obesity.

CONTEXT: Obesity and diabetes during pregnancy are associated with increased insulin resistance and higher neonatal adiposity. In turn, insulin resistance triggers inflammatory pathways with accumulation of placental cytokines. OBJECTIVE: To determine placental signals that translate into development of excess adipose tissue, we investigated the role of phospholipases A2 (PLA2) as targets of inflammatory mediators. SETTING: The study was conducted at Case Western Reserve University, Department of Reproductive Biology. SUBJECTS: Volunteers gave informed written consent in accordance with the Institutional Review Board guidelines. Placenta and cord blood samples were obtained at the time of elective cesarean section in 15 term pregnancies. INTERVENTION: Neonatal anthropometric measurements were performed within 48 h of delivery. Placentas were grouped based on neonatal percentage body fat as obese (body fat > or = 16%) and lean control (body fat < or = 8%). MAIN OUTCOME MEASURES: The primary outcomes were placenta PLA2 expression and fatty acid concentration. RESULTS: Expression of PLA2G2A and PLA2G5, the main placenta phospholipases, was greater (P < 0.05) in placenta of obese compared with control neonates and was associated with increased 20:3 and 20:5 omega-3 polyunsaturated fatty acids. TNF-alpha and leptin content was increased 3-fold in placenta of obese neonates. TNF-alpha and leptin both induced a time-dependent activation of PLA2G2 and PLA2G5 in placental cells. CONCLUSION: Accumulation of omega-3 fatty acids through secretory PLA2 activation is associated with high neonatal adiposity. We propose that the generation of placental lipid mediators through TNF-alpha and leptin stimulation represents a key mechanism to favor excess fetal fat accretion.

Adult↗

MAPL regulates gasdermin-mediated release of mtDNA from lysosomes to drive pyroptotic cell death.

Mitochondrial control of cell death is of central importance to disease mechanisms from cancer to neurodegeneration. Mitochondrial anchored protein ligase (MAPL) is an outer mitochondrial membrane small ubiquitin-like modifier ligase that is a key determinant of cell survival, yet how MAPL controls the fate of this process remains unclear. Combining genome-wide functional genetic screening and cell biological approaches, we found that MAPL induces pyroptosis through an inflammatory pathway involving mitochondria and lysosomes. MAPL overexpression promotes mitochondrial DNA trafficking in mitochondrial-derived vesicles to lysosomes, which are permeabilized in a process requiring gasdermin pores. This triggers the release of mtDNA into the cytosol, activating the DNA sensor cGAS, required for cell death. Additionally, multiple Parkinson's disease-related genes, including VPS35 and LRRK2, also regulate MAPL-induced pyroptosis. Notably, depletion of MAPL, LRRK2 or VPS35 inhibited inflammatory cell death in primary macrophages, placing MAPL and the mitochondria-lysosome pathway at the nexus of immune signalling and cell death.

Lysosomes↗

CD14 and toll-like receptor 4: a link between infection and acute coronary events?

The CD14 receptor is a pattern recognition molecule in the innate immune response against microorganisms and other exogenous and endogenous stress factors. The most important CD14 signalling co-receptor is toll-like receptor 4 (TLR4), which activates, among others, the nuclear factor kappaB (NF-kappaB) inflammatory pathway. Besides its role in innate immunity and host defence, the proinflammatory cytokines expressed upon TLR4/NF-kappaB pathway activation exert proatherogenic effects. The CD14 C(-260)T promoter and TLR4 Asp299Gly functional polymorphisms have been recently implicated in the development of cardiovascular events, suggesting that the genetically determined inflammatory response against pathogens or their antigens may have a major role in atherogenesis and subsequent acute events. Is the association of these polymorphisms with cardiovascular disease more evidence for the implication of infection, especially by Gram negative bacteria, in the development of acute coronary events? This article reviews the molecular basis, biological functions, and clinical implications of the CD14/TLR4 polymorphisms in the development of cardiovascular events.

Cell Communication↗

Anti-inflammatory actions of the neuroimmunomodulator alpha-MSH.

alpha-melanocyte-stimulating hormone (alpha-MSH) is an endogenous neuroimmunomodulatory peptide that inhibits fever and all major forms of experimental inflammation. In humans, concentrations of alpha-MSH are increased at sites of inflammation, and in plasma in inflammatory disorders and after infection of endotoxin. The effects of this 'anti-cytokine' peptide are mediated through alpha-MSH receptors and regulatory circuits in macrophages and neutrophils, and through descending neural anti-inflammatory pathways that originate from alpha-MSH receptors on neurons within the brain.

Animals↗

A comparison of the anti-inflammatory properties of intranasal corticosteroids and antihistamines in allergic rhinitis.

Allergic rhinitis manifests itself clinically due to the local release of mediators from activated cells within the nasal mucosa. Treatment strategies aim either to reduce the effects of these mediators on the sensory neural and vascular end organs, or to reduce the tissue accumulation of the activated cells that generate them. Corticosteroids intervene at a number of steps in the inflammatory pathway, and, by reducing the release of cytokines and chemokines, inhibit cell recruitment and activation. These effects are evident both in vivo and in vitro. While antihistamines also have some anti-inflammatory effects in vitro, these require higher concentrations than with corticosteroids and are not consistently reproduced in vivo. In addition, although antihistamines and corticosteroids might appear to have complementary mechanisms of action, clinical trials suggest that their co-administration does not confer any additional long-term benefits compared with that achieved with corticosteroids alone. Topical corticosteroids are therefore the preferred anti-inflammatory therapy for persistent allergic rhinitis.

Administration, Intranasal↗

Jak/STAT/SOCS signaling circuits and associated cytokine-mediated inflammation and hypertrophy in the heart.

Cytokines are important mediators of cardiac disease. Accumulating evidence indicates that members of the interleukin-6 family of cytokines promote cardiac hypertrophy through the activation of the Janus kinase-signal transducer and activator of transcription (Jak/STAT) pathway. Aberrant Jak/STAT signaling may promote progression from hypertrophy to heart failure. Suppressor of cytokine signaling (SOCS) proteins are underexplored, negative regulators of Jak/STAT signaling. SOCS proteins may also interact with other inflammatory pathways known to affect cardiac function. A better understanding of the therapeutic potential of these proteins may lead to the controlled progression of heart failure and the limitation of myocardial depression. This review summarizes the cardiophysiological effect of the IL-6 cytokine family, outlines the mechanistic pathway of Jak/STAT signaling, explores the regulatory role of SOCS proteins in the heart, and discusses the potential of using SOCS proteins clinically.

Animals↗

The role of phospholipases in lipid modification and atherosclerosis.

Phospholipases have received wide attention as it has become clear that several isoforms of the phospholipase family play a role in onset and progression of atherosclerosis. The release of free fatty acids (FFA) and lysophospholipids (lysoPL) provide metabolites for various inflammatory pathways, and this has been considered the main mechanism of phospholipase-driven inflammation. However, generation of FFA and lysoPL are only part of the story. The induction of low-density phospholipoprotein (LDL) aggregation and accumulation, receptor binding, co-regulation with cyclooxygenase (COX) and lip-oxygenase (LO) pathways, internalization through heparan sulfate proteoglycan (HSPG) shuttling, and crosstalk between phospholipases all play a role in atherosclerosis.Group IIA phospholipase has long been considered a key enzyme in the initiation of various inflammatory diseases, but new data also indicate a role in the subsequent resolution of inflammatory processes. Recently, secreted group V and group X phospholipase and platelet activating factor acetylhydrolase (PAF-AH) are also recognized as important enzymes in atherosclerosis, modifying LDL and leading to lipid accumulation. The phospholipases and their function in atherosclerosis are not fully under-stood. Future investigations can deliver better insight in the complex role of these enzymes. The present review summarizes the current state of phospholipase research related to atherosclerosis.

Animals↗

The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation.

Acute graft-versus-host disease (GVHD), the major complication of allogeneic bone marrow transplantation (BMT), limits the application of this curative but toxic therapy. Studies of inflammatory pathways involved in GVHD in animals have shown that the gastrointestinal (GI) tract plays a major role in the amplification of systemic disease. Damage to the GI tract increases the translocation of inflammatory stimuli such as endotoxin, which promotes further inflammation and additional GI tract damage. The GI tract is therefore critical to the propagation of the "cytokine storm" characteristic of acute GVHD. Experimental approaches to the prevention of GVHD include reducing the damage to the GI tract by fortification of the GI mucosal barrier through novel "cytokine shields" such as IL-11 or keratinocyte growth factor. Such strategies have reduced GVHD while preserving a graft-versus-leukemia effect in animal models, and they now deserve formal testing in carefully designed clinical trials. (Blood. 2000;95:2754-2759)

Animals↗