Role of lactoferrin in development of inflammation

During acute inflammation, immune homeostasis is lost leading to destructive immunopathology. Homeostasis is normally dependent upon coordinated interactions among the various lymphoid, phagocytic and somatic cells that comprise the immune system. In general, these interactions are tightly regulated to obtain a balance between mechanisms necessary to eliminate harmful pathogens, and overaggressive responses leading to destruction of host tissue. Activation of immunoeffector cells results in pro-inflammatory cytokine up-regulation which in turn also activates the vascular endothelium. Through complex signaling, a positive feedback circuit is established which amplifies and sustains the activity of the inflammatory response resulting in the release of other cytokines and related molecules. If these responses are activated in an uncontrolled fashion with dissemination via the circulation, over the period of time, organs distant from the initial insult can be affected to produce multiple organ failure. Lactoferrin, an iron-binding glycoprotein, is considered an important mediator in host defense against the environmental insults in mammals. By virtue of iron sequestration lactoferrin can control the development of many oxidative stress-driven responses. The purpose of this review is to provide a comprehensive summary of research regarding lactoferrin and its role in homeostasis.     

Inflammation and cardiovascular disease

Cardiovascular disease (CVD) has been associated with the so-called traditional risk factors, such as hypertension, hypercholesterolemia and cigarette smoking. Chronic inflammation, exemplified by elevated high sensitivity C-reactive protein, has been added to these risk factors for CVD as non-traditional risk factor. There are two aspects in this association. The first is whether inflammation plays a pathogenic role in traditional risk factors-mediated CVD or it is just an epiphenomenon. The second is whether chronic inflammation caused by an inflammatory disease has any impact on CVD. Accumulated data have shown that inflammation has a central and inciting role in the development of atherosclerosis leading to increased CVD risk. How inflammation contributes to CVD is a topic of continuous research where mechanisms involving both innate and adaptive immune pathways are involved. Endothelial dysfunction, oxidative stress in vascular endothelial cells, macrophage accumulation, formation of inflammasome, production of tumor necrosis factor (TNF)-a, IL-1 and IL-6 characterize the inflammatory process leading to atherogenesis. Recently clonal hematopoiesis of indeterminate potential represents a surprising and novel mechanism underlying atherogenesis. Data from chronic rheumatic inflammatory diseases exemplify the complexity of mechanisms leading to increased CVD, while they also provide evidence that anti-inflammatory biologic drugs, such as anti-TNF and anti-IL6 agents, could control atherogenesis and ameliorate CVD risk. Recent groundbreaking work using biologic anti-IL-1b therapy to treat men and women who have had a prior heart attack provides the best proof of the pathogenic contribution of inflammation in the development of CVD.     

(n-3) Fatty acids alleviate adipose tissue inflammation and insulin resistance: mechanistic insights

Obesity is associated with the metabolic syndrome, a significant risk factor for developing type 2 diabetes and cardiovascular diseases. Chronic low-grade inflammation occurring in the adipose tissue of obese individuals is causally linked to the pathogenesis of insulin resistance and the metabolic syndrome. Although the exact trigger of this inflammatory process is unknown, adipose tissue hypoxia, endoplasmic reticular stress, and saturated fatty acid-mediated activation of innate immune processes have been identified as important processes in these disorders. Furthermore, macrophages and T lymphocytes have important roles in orchestrating this immune process. Although energy restriction leading to weight loss is the primary dietary intervention to reverse these obesity-associated metabolic disorders, other interventions targeted at alleviating adipose tissue inflammation have not been explored in detail. In this regard, (n-3) PUFA of marine origin both prevent and reverse high-fat-diet-induced adipose tissue inflammation and insulin resistance in rodents. We provide an update on the pathogenesis of adipose tissue inflammation and insulin resistance in obesity and discuss potential mechanisms by which (n-3) PUFA prevent and reverse these changes and the implications in human health.     

Inflammatory Mechanisms: The Molecular Basis of Inflammation and Disease

Inflammation participates importantly in host defenses against infectious agents and injury, but it also contributes to the pathophysiology of many chronic diseases. Interactions of cells in the innate immune system, adaptive immune system, and inflammatory mediators orchestrate aspects of the acute and chronic inflammation that underlie diseases of many organs. A coordinated series of common effector mechanisms of inflammation contribute to tissue injury, oxidative stress, remodeling of the extracellular matrix, angiogenesis, and fibrosis in diverse target tissues. Atherosclerosis provides an example of a chronic disease that involves inflammatory mechanisms. Recruitment of blood leukocytes characterizes the initiation of this disease. Its progression involves many inflammatory mediators, modulated by cells of both innate and adaptive immunity. The complications of established atheroma, including plaque disruption and thrombosis, also intimately involve inflammation. Mastery of the inflammatory response should aid the development of novel strategies to predict disease susceptibility, target and monitor therapies, and ultimately develop new approaches to the prevention and treatment of chronic diseases associated with aging, such as atherosclerosis.     

Proinflammatory Cytokines,Aging, and Age-Related Diseases

Inflammation is a physiological process that repairs tissues in response to endogenous or exogenous aggressions. Nevertheless, a chronic state of inflammation may have detrimental consequences. Aging is associated with increased levels of circulating cytokines and proinflammatory markers. Aged-related changes in the immune system, known as immunosenescence, and increased secretion of cytokines by adipose tissue, represent the major causes of chronic inflammation. This phenomenon is known as “inflamm-aging.” High levels of interleukin (IL)-6, IL-1, tumor necrosis factor-α, and C-reactive protein are associated in the older subject with increased risk of morbidity and mortality. In particular, cohort studies have indicated TNF-α and IL-6 levels as markers of frailty. The low-grade inflammation characterizing the aging process notably concurs at the pathophysiological mechanisms underlying sarcopenia. In addition, proinflammatory cytokines (through a variety of mechanisms, such as platelet activation and endothelial activation) may play a major role in the risk of cardiovascular events. Dysregulation of the inflammatory pathway may also affect the central nervous system and be involved in the pathophysiological mechanisms of neurodegenerative disorders (eg, Alzheimer disease).The aim of the present review was to summarize different targets of the activity of proinflammatory cytokines implicated in the risk of pathological aging.     

Sepsis: the inflammatory foundation of pathophysiology and therapy

Sepsis, defined as an infection accompanied by inflammation, is a complex disease process wherein the body's response to a pathogen is amplified far beyond the initial site of infection. The process begins when pathogen-associated molecular patterns on the bacteria or other pathogens induce an inflammatory cascade in the host. In the United States, it is estimated that every minute a patient with severe sepsis or septic shock presents to an emergency department and that > 751 000 cases of severe sepsis occur annually, resulting in an estimated 215 000 deaths. A rapid progression of illness severity from sepsis to severe sepsis to septic shock frequently occurs, driven by the body's inflammatory and anti-inflammatory responses to a pathogen, making sepsis a condition requiring timely intervention. The clinical management of severe sepsis and septic shock has evolved dramatically over the past decade and these new therapeutic approaches have been built on a deeper understanding of the natural evolution of sepsis. This article examines the underlying pathophysiological mechanisms of sepsis to help explain the clinical signs and symptoms manifested by severe sepsis patients. It also examines the significance of current proposed treatment strategies, including early goal-directed therapy, from a pathophysiological and inflammatory perspective.     

Obesity-Associated Inflammation: Does Curcumin Exert a Beneficial Role?

Curcumin is a lipophilic polyphenol, isolated from the plant turmeric of Curcuma longa. Curcuma longa has always been used in traditional medicine in Asian countries because it is believed to have numerous health benefits. Nowadays it is widely used as spice component and in emerging nutraceutical food worldwide. Numerous studies have shown that curcumin possesses, among others, potential anti-inflammatory properties. Obesity represents a main risk factor for several chronic diseases, including type 2 diabetes, cardiovascular disease, and some types of cancer. The establishment of a low-grade chronic inflammation, both systemically and locally in adipose tissue, occurring in obesity most likely represents a main factor in the pathogenesis of chronic diseases. The molecular mechanisms responsible for the onset of the obesity-associated inflammation are different from those involved in the classic inflammatory response caused by infections and involves different signaling pathways. The inflammatory process in obese people is triggered by an inadequate intake of nutrients that produces quantitative and qualitative alterations of adipose tissue lipid content, as well as of various molecules that act as endogenous ligands to activate immune cells. In particular, dysfunctional adipocytes secrete inflammatory cytokines and chemokines, the adipocytokines, able to recruit immune cells into adipose tissue, amplifying the inflammatory response also at systemic level. This review summarizes the most recent studies focused at elucidating the molecular targets of curcumin activity responsible for its anti-inflammatory properties in obesity-associated inflammation and related pathologies.     

Micronutrients and host resistance to viral infection

Previous work in our laboratory demonstrated that a virus could undergo rapid mutation in a host deficient in Se, leading to a normally avirulent virus acquiring virulence due to genome changes. Once these mutations occur, even a host with adequate Se-nutriture is susceptible to the newly virulent virus. What influence does the deficiency in Se have on the immune response of the host? Infection with myocarditic strains of coxsackievirus induces an inflammatory response in the cardiac tissue. It is this immune response that induces the heart damage, rather than direct viral effects on the heart tissue. Chemokines are chemo-attractant molecules that are secreted during an infection in order to attract immune cells to the site of the injury, and have been found to be important for the development of coxsackievirus-induced myocarditis. We found that a deficiency in Se influences the expression of mRNA for the chemokine monocyte chemo-attractant protein-1, which may have implications for the development of myocarditis in the Se-deficient host. Expression of mRNA for interferon-gamma was also greatly decreased in the Se-deficient animal. Thus, a deficiency in Se can have profound effects on the host as well as on the virus itself. How the alteration of the immune response of the Se-deficient animal affects the development of the virulent genotype remains to be answered.     

Obesity, inflammation and the immune system

Obesity shares with most chronic diseases the presence of an inflammatory component, which accounts for the development of metabolic disease and other associated health alterations. This inflammatory state is reflected in increased circulating levels of pro-inflammatory proteins, and it occurs not only in adults but also in adolescents and children. The chronic inflammatory response has its origin in the links existing between the adipose tissue and the immune system. Obesity, like other states of malnutrition, is known to impair the immune function, altering leucocyte counts as well as cell-mediated immune responses. In addition, evidence has arisen that an altered immune function contributes to the pathogenesis of obesity. This review attempts to briefly comment on the various plausible explanations that have been proposed for the phenomenon: (1) the obesity-associated increase in the production of leptin (pro-inflammatory) and the reduction in adiponectin (anti-inflammatory) seem to affect the activation of immune cells; (2) NEFA can induce inflammation through various mechanisms (such as modulation of adipokine production or activation of Toll-like receptors); (3) nutrient excess and adipocyte expansion trigger endoplasmic reticulum stress; and (4) hypoxia occurring in hypertrophied adipose tissue stimulates the expression of inflammatory genes and activates immune cells. Interestingly, data suggest a greater impact of visceral adipose tissue and central obesity, rather than total body fat, on the inflammatory process. In summary, there is a positive feedback loop between local inflammation in adipose tissue and altered immune response in obesity, both contributing to the development of related metabolic complications.     

Gut Microbiota and Probiotics/Synbiotics for Modulation of Immunity in Critically Ill Patients

Patients suffering from critical illness have host inflammatory responses against injuries, such as infection and trauma, that can lead to tissue damage, organ failure, and death. Modulation of host immune response as well as infection and damage control are detrimental factors in the management of systemic inflammation. The gut is the motor of multiple organ failure following injury, and it is recognized that gut dysfunction is one of the causative factors of disease progression. The gut microbiota has a role in maintaining host immunity, and disruption of the gut microbiota might induce an immunosuppressive condition in critically ill patients. Treatment with probiotics and synbiotics has been reported to attenuate systemic inflammation by maintaining gut microbiota and to reduce postoperative infectious complications and ventilator-associated pneumonia. The administration of prophylactic probiotics/synbiotics could be an important treatment option for preventing infectious complications and modulating immunity. Further basic and clinical research is needed to promote intestinal therapies for critically ill patients.     

Diet/Genetic Interactions and Their Effects on Inflammatory Markers

The importance of a healthy diet to living well is well recognized. A growing array of experimental, epide-miological, and clinical studies have revealed an association between pro-inflammatory responses and the progression of numerous serious disease states, including the metabolic syndrome, type 2 diabetes, and cardiovascular diseases. Further studies have established a "diet/genetic interaction" that further modulates markers of inflammation, producing both positive and negative effects, depending on the net changes in gene expression. Yet, there are few studies that reveal the mechanisms underlying this modulation of the inflammatory response. Highlighted here are several such recent and ongoing studies that investigate the mechanisms underlying the effects of diet/genetic interactions on inflammatory biomarkers, followed by a discussion of to what extent these interactions may translate into healthier aging and increased longevity. Whether these interactions translate into healthier aging and increased longevity remains to be determined; however, the prospects are enticing.     

Etiopathogenesis of inflammatory bowel diseases

The pathogenesis of IBD is only partly understood; various environmental and host (e.g. genetic-, epithelial-, immune and non-immune) factors are involved. It is a multifactorial polygenic disease with probable genetic heterogeneity, some genes are associated with IBD itself, while others increase the risk of ulcerative colitis (UC) or Crohn's disease (CD) or are associated with disease location and/or behaviour. The role of environmental factors, in particular, enteric antigens, smoking and non-steroid anti-inflammatory drug use has been well established. However uptil now no proof of a role of any unique pathogenic bacteria or special dietary and/or psychosocial factor has been identified. In this hypothesis, the disease may develop in a genetically predisposed host as a consequence of disregulated immune response to environmental, in particular, enteric antigens, resulting in a continuous immune-mediated inflammation (in CD predominantly Th-1, in UC a modified Th-2 mechanisms are involved) and not in tolerance. As a consequence, the permeability of mucosa and the antigen challenge increases, in contrast, the disregulated immune response is unable to downregulate the inflammatory process. This will result in a continuous inflammation and tissue damage. The pathogenesis of CD is thought to be mainly an antigen driven, T-lymphocyte dependent process, while in UC the role of epithelial factors and activated granulocytes are essential.     

Complement-mediated microvascular injury and thrombosis in the pathogenesis of severe COVID-19: A review

Coronavirus disease 2019 (COVID-19) causes acute microvascular thrombosis in both venous and arterial structures which is highly associated with increased mortality. The mechanisms leading to thromboembolism are still under investigation. Current evidence suggests that excessive complement activation with severe amplification of the inflammatory response (cytokine storm) hastens disease progression and initiates complement-dependent cytotoxic tissue damage with resultant prothrombotic complications. The concept of thromboinflammation, involving overt inflammation and activation of the coagulation cascade causing thrombotic microangiopathy and end-organ damage, has emerged as one of the core components of COVID-19 pathogenesis. The complement system is a major mediator of the innate immune response and inflammation and thus an appealing treatment target. In this review, we discuss the role of complement in the development of thrombotic microangiopathy and summarize the current data on complement inhibitors as COVID-19 therapeutics.     

Xenobiotic considerations for the development of autoimmune liver diseases: bad genes and bad luck.

The etiologic origins of autoimmune disease remain an enigma. Although considerable information on the mechanisms of immunopathology has been acquired, in part from murine models, such mechanisms have yet to be substantiated in human autoimmune disease. This absence of validation is especially true for organ-specific diseases like those affecting the liver. In this review we focus on the putative role of xenobiotics as inducing agents for autoimmune liver pathology. In particular, we discuss the autoantibody immune response, the humoral hallmark of autoimmune disease, as well as cellular immune responses. We believe that exposure to environmental factors, namely xenobiotics, is the initiating straw that breaks the camel's back, leading to the loss of tolerance to self proteins in genetically susceptible hosts. The end result is a perpetuating process that is determined by the governing features of the genetics of the host and by exposure to the inciting environmental agent. Interestingly, the liver, an organ that plays a major role in immune tolerance, can itself become the target of autoreactivity and immune destruction.     

Evidence for genetic variation as a factor in maintaining health

For many chronic diseases, the influence of genetics is subtle and complex and does not conform to simple Mendelian patterns of inheritance as is seen with single-gene disorders. Genetic variation can influence the propensity for the initiating event, the progression to a clinical disease state, and the trajectory of disease. One example of how genetic variations may affect complex diseases is provided by the interleukin 1 family of cytokines. This cytokine family plays a key role in mediating inflammation, which is a central component of many chronic diseases, including coronary artery disease and rheumatoid arthritis. Recent research has identified many sequence variations in the regulatory DNA of the genes coding for important members of the interleukin 1 family, and these variations are associated with differential effects on the inflammatory response. These in turn alter the risk of some diseases in which inflammation plays a role and also affect physiologic responses, such as the inflammatory response to exercise. As this new genetic knowledge is developed and extended, it may be possible to make health care interventions at an earlier stage, before clinical disease is established, rather than after tissues have been permanently damaged.     

Wound healing reaction: A switch from gestation to senescence

The repair of wounded tissue during postnatal life could be associated with the upregulation of some functions characteristic of the initial phases of embryonic development. The focusing of these recapitulated systemic functions in the interstitial space of the injured tissue is established through a heterogeneous endothelial barrier which has excretory-secretory abilities which in turn, would induce a gastrulation-like process. The repair of adult tissues using upregulated embryonic mechanisms could explain the universality of the inflammatory response against injury, regardless of its etiology. However, the early activation after the injury of embryonic mechanisms does not always guarantee tissue regeneration since their long-term execution is mediated by the host organism.     

Omega-3 fatty acids and inflammatory processes

Long chain fatty acids influence inflammation through a variety of mechanisms; many of these are mediated by, or at least associated with, changes in fatty acid composition of cell membranes. Changes in these compositions can modify membrane fluidity, cell signaling leading to altered gene expression, and the pattern of lipid mediator production. Cell involved in the inflammatory response are typically rich in the n-6 fatty acid arachidonic acid, but the contents of arachidonic acid and of the n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can be altered through oral administration of EPA and DHA. Eicosanoids produced from arachidonic acid have roles in inflammation. EPA also gives rise to eicosanoids and these often have differing properties from those of arachidonic acid-derived eicosanoids. EPA and DHA give rise to newly discovered resolvins which are anti-inflammatory and inflammation resolving. Increased membrane content of EPA and DHA (and decreased arachidonic acid content) results in a changed pattern of production of eicosanoids and resolvins. Changing the fatty acid composition of cells involved in the inflammatory response also affects production of peptide mediators of inflammation (adhesion molecules, cytokines etc.). Thus, the fatty acid composition of cells involved in the inflammatory response influences their function; the contents of arachidonic acid, EPA and DHA appear to be especially important. The anti-inflammatory effects of marine n-3 PUFAs suggest that they may be useful as therapeutic agents in disorders with an inflammatory component.     

The Potential Role of Probiotics in Cancer Prevention and Treatment

The human gut microbiota has a significant effect on many aspects of human physiology such as metabolism, nutrient absorption, and immune function. Imbalance of the microbiota has been implicated in many disorders including inflammatory bowel disease, obesity, asthma, psychiatric illnesses, and cancers. As a kind of functional foods, probiotics have been shown to play a protective role against cancer development in animal models. Clinical application of probiotics indicated that some probiotic strains could diminish the incidence of postoperative inflammation in cancer patients. Chemotherapy or radiotherapy-related diarrhea was relieved in patients who were administered oral probiotics. The present review summarizes the up-to-date studies on probiotic effects and the underlying mechanisms related to cancer. At present, it is commonly accepted that most commercial probiotic products are generally safe and can improve the health of the host. By modulating intestinal microbiota and immune response, some strains of probiotics can be used as an adjuvant for cancer prevention or/and treatment.     

Protective Role of Interleukin-10 in Ozone-Induced Pulmonary Inflammation

Background

The mechanisms underlying ozone (O₃)-induced pulmonary inflammation remain unclear. Interleukin-10 (IL-10) is an anti-inflammatory cytokine that is known to inhibit inflammatory mediators.

Objectives

We investigated the molecular mechanisms underlying interleuken-10 (IL-10)–mediated attenuation of O₃-induced pulmonary inflammation in mice.

Methods

Il10-deficient (Il10^−/−) and wild-type (Il10^+/+) mice were exposed to 0.3 ppm O₃ or filtered air for 24, 48, or 72 hr. Immediately after exposure, differential cell counts and total protein (a marker of lung permeability) were assessed from bronchoalveolar lavage fluid (BALF). mRNA and protein levels of cellular mediators were determined from lung homogenates. We also used global mRNA expression analyses of lung tissue with Ingenuity Pathway Analysis to identify patterns of gene expression through which IL-10 modifies O₃-induced inflammation.

Results

Mean numbers of BALF polymorphonuclear leukocytes (PMNs) were significantly greater in Il10^−/− mice than in Il10^+/+ mice after exposure to O₃ at all time points tested. O₃-enhanced nuclear NF-κB translocation was elevated in the lungs of Il10^−/− compared with Il10^+/+ mice. Gene expression analyses revealed several IL-10–dependent and O₃-dependent mediators, including macrophage inflammatory protein 2, cathepsin E, and serum amyloid A3.

Conclusions

Results indicate that IL-10 protects against O₃-induced pulmonary neutrophilic inflammation and cell proliferation. Moreover, gene expression analyses identified three response pathways and several genetic targets through which IL-10 may modulate the innate and adaptive immune response. These novel mechanisms of protection against the pathogenesis of O₃-induced pulmonary inflammation may also provide potential therapeutic targets to protect susceptible individuals.