Heart disease is a leading cause of global morbidity and mortality. Cardiovascular disease, most of which occurs secondary to atherosclerosis, accounted for more than one-third of all deaths in Australia in 2006, and this is likely to increase as the population ages and the incidence of diabetes rises. Ongoing research has led to the development of international guidelines for the prevention and treatment of ischaemic heart disease (IHD). Recent research has highlighted the inflammatory basis of atherosclerosis and provided hope of new therapeutic targets in IHD, including treatments able to cause disease regression. This paper will review the role of the immune system in the pathogenesis of heart disease. Recent research on the interaction between the immune system and heart disease has focused on the role of T lymphocytes in coronary heart disease. This paper will focus on immunity and atherosclerosis. In addition, we will review the cellular mechanisms by which lymphocytes may injure the myocardium and cause disease.
Herein we review some of the existing knowledge on how the intracellular signaling mediator cyclic adenosine monophosphate (cAMP) regulates mechanisms involved in sepsis and septic shock, focusing on inflammation and hemodynamics. Elevating cAMP by inhibition of the cAMP-hydrolyzing phosphodiesterases has been reported to protect organ function in animal models of systemic inflammation and endotoxic shock and, likewise, increased survival from septic shock has been reported in mice deficient in specific cAMP phosphodiesterase isoforms. The cAMP signaling pathway modulates inflammation by attenuating proinflammatory cytokine release, neutrophil infiltration, degranulation and cytotoxic responses. cAMP also controls hemodynamics by regulating cardiovascular function, endothelial barrier function and platelet activation. There is a need to obtain a more detailed understanding of cAMP signaling, and to further evaluate the future potential of sepsis treatment targeting this pathway.
Although the hemodynamic profile of sepsis is characterized by a high cardiac output state, there is clear evidence of myocardial dysfunction in patients with severe sepsis and septic shock. Cardiac abnormalities in sepsis include various degrees of left ventricular systolic dysfunction, left ventricular diastolic dysfunction, and right ventricular dysfunction. Possible underlying mechanisms include direct negative inotropic effects of circulating depressant substances, altered G-protein coupling, myocardial β1-receptor desensitization, and cytopathic hypoxia due to microcirculatory and metabolic abnormalities of the cardiomyocytes. We discuss herein the conflicting findings of the heterogeneous studies conducted in this field and, based on clinical data and findings from experimental work, hypothesize on the underlying pathophysiology and the mechanisms of established and innovative therapies.
Pathology has evolved over the past 30 years to incorporate molecular analysis of tissue samples for the assessment of disease states. With the advent of molecular pathology has come the development of new technologies to evaluate the tissue specimen at the molecular level. In this review, we will focus on proteomic analysis of human tissues. The importance of tissue preservation as well as the specific isolation of cell populations via microdissection will be addressed. In addition, the molecular evaluation of the tissue specimen with current proteomic techniques, including 2D polyacrylamide gel electrophoresis, Western blotting, protein arrays and mass spectrometry, will also be discussed. Finally, two new technologies will be introduced: direct tissue mass spectrometry and layered expression scanning. These new methods maintain the 2D architecture of the tissue throughout the proteomic analysis process, providing additional information that is typically lost with microdissected samples. The challenging application of these new molecular technologies to the analysis of human tissue specimens is essential for the better understanding of diseases.
Marked changes in thyroid hormone levels occur in critical illness and multiple organ dysfunction syndrome (MODS), with a decrease in the active hormone T3 and an increase in the inactive metabolite rT3. The magnitude of these changes is related to the severity of the disease. Studies addressing the thyrotropic axis in critical illness do not make a clear distinction between patients with and without MODS. However, a distinction can be made between the acute and the more chronic phase of critical illness, and it can be assumed that patients who require intensive care for several days will have some degree of MODS. This review therefore focuses on the thyroid axis in patients receiving intensive care for several days. The mechanisms behind the observed changes, the potential positive and/or negative effects of them and their possible therapeutic consequences will be discussed.
Neutrophils [polymorphonuclear leukocytes (PMNs)] express several purinergic receptors, including the nucleotide receptors P2Y2 and P2X7 and the adenosine receptor subtypes A1, A2A and A3. Activation of these receptors modulates PMN function and ultimately, in concert with other cells, affects the host's innate inflammatory response. PMN activities that can be altered by purinergic receptor stimulation include adhesion, aggregation, migration, phagocytosis, microbicidal function, release of tissue-damaging products and apoptosis. Interventions that alter PMN purinergic receptor stimulation are being developed to reduce organ dysfunction in conditions such as sepsis, ischemia–reperfusion injury and the acute respiratory distress syndrome.
This article reviews studies dealing with gut barrier dysfunction following major trauma and alcohol exposure. An association between alcohol exposure and traumatic injury has been recognized in many studies. The gut is the major reservoir of bacteria within the body but, under healthy conditions, it maintains a barrier which prevents these bacteria from crossing the intestinal lumen. The findings reviewed herein indicate that this barrier is lost in conditions such as major trauma and alcohol exposure. Furthermore, studies also indicate that alcohol intoxication at the time of injury causes a further deterioration in intestinal barrier function as determined by intestinal permeability and bacterial translocation. A precise mechanism for impaired barrier function following alcohol exposure, either alone or in combination with major trauma or burn injury, remains unknown. However, the findings discussed in this article indicate that this could result from: (i) an increase in bacterial growth; (ii) a decrease in blood flow; (iii) an increase in inflammatory mediators such as cytokines and chemokines; and (iv) an increase in the release of superoxide anions and proteases by neutrophils.
Protein phosphorylation is a key event in endothelial cell signaling and barrier regulation. We previously demonstrated that the non-muscle myosin light chain kinase (nmMLCK) isoform present in endothelium (1914aa) is a multi-functional enzyme which drives the participation of the actin cytoskeleton in vascular barrier regulation, trafficking of inflammatory cells into the lung, and susceptibility to sepsis-induced acute lung injury. The activity of the nmMLCK isoform is differentially regulated by both Ser/Thr and Tyr phosphorylation; however, cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA)-mediated nmMLCK phosphorylation exerts paradoxical effects on kinase activity depending on the exact Ser/Thr sites. To address this conundrum, we mapped in vitro phosphorylation sites of nmMLCK catalyzed by the catalytic unit of PKA using data-dependent nano-liquid chromatography tandem mass spectrometry. High mass-accuracy MS and optimized biochemical protocols identified 26 novel nmMLCK1 PKA phosphorylation sites, including 11 located within the unique nmMLCK N-terminus and four (T335, S365, S947, and T1230) located within putative SH3-binding domains, as well as the known PKA-mediated nmMLCK phosphorylation site (S1208). Further structure/function analysis of the functional effects of these novel phosphorylation events may provide important insights into the regulation of nmMLCK activity and barrier regulation by cAMP-dependent processes.
In addition to their critical role in embryogenesis of the kidney, members of the transforming growth factor (TGF)-β superfamily direct a number of pathways important in the maintenance of homeostasis in the differentiated kidney. TGF-β family members also play an important role in cell-cycle regulation. Through induction of cyclin-dependent kinase inhibitors, TGF-β promotes a hypertrophic response of renal tubular epithelial cells and glomerular mesangial cells. This TGF-β-driven hypertrophic response, which occurs in diabetic nephropathy, may have deleterious effects on the kidney. In contrast, many human cancers are associated with loss of the growth inhibitory effects of TGF-β. TGF-β may promote or inhibit inflammation, an outcome which appears to depend on the cell type(s) involved and on potential interactions with other signaling pathways that regulate inflammatory responses. In recent studies, TGF-β has been implicated as a key mediator of the epithelial to mesenchymal transition, a process through which epithelial cells acquire characteristics of myofibroblasts which synthesize and deposit extracellular matrix macromolecules and lead to the development of fibrosis, a characteristic feature of chronic renal disease irrespective of etiology. In this brief overview, we highlight recent advances in our understanding of TGF-β signaling that contribute to the development and progression of chronic renal disease.
Chronic obstructive pulmonary disease (COPD) is a complex disorder predominantly affecting smokers and is characterized by progressive airflow obstruction that is largely irreversible. Approximately 25% of smokers are believed to be susceptible to developing the disease, suggesting that there are at present unknown genetic, epigenetic and/or environmental factors which underlie an individual's risk for developing the disease. COPD is a multifactorial disease and susceptibility is therefore likely to be determined by the expression of a number of allelic variants that leave an individual less capable of handling the damaging effects of chronic smoking. It is proposed herein that intrinsic aerobic (exercise) capacity is the primary trait which determines an individual's risk for developing this disease. This polygenetic characteristic comprises an individual's ability to metabolize oxygen and detoxify its reactive species. Pathways regulating these processes are damaged by smoking; thus individuals with low aerobic capacity may be more likely to develop smoking-induced lung damage, eventually leading to irreversible pathologies which cause airflow obstruction.
5-Lipoxygenase (5-LO) is an important enzyme that dominates the metabolism of arachidonic acid and the synthesis of leukotrienes, of which leukotriene B4 (LTB4) is suggested to be one of the most potent chemoattractants and activators of leukocytes. 5-LO is normally limited to hematopoetic cells, e.g. granulocytes and macrophages, where LTB4 is produced. Leukotrienes play an important role in the innate defense system, in the antimicrobial defense system, and in intercellular signaling. Under pathophysiological conditions, overproduction of LTB4 was noted in multiple cells. It is known that 5-LO and its production of LTB4 are involved in the maintenance of normal host defense, initiation of inflammation, migration of leukocytes, development of endothelial barrier dysfunction, hyperresponsiveness of smooth muscle cells, stimulation of mucus secretion, reduction of mucociliary clearance, and tissue remodeling. In order to understand the role of 5-LO and its production in functions of the innate host defense...
The prevalence of hepatic dysfunction was thought to be ≈ 1% in intensive care unit (ICU) patients, but is now being recognized to be > 10%. Mortality and length of ICU stay are directly affected by hepatic dysfunction, raising the need for a better understanding of this disorder in order to develop therapeutic options that go beyond the current practice of supportive care. The etiologies of hypoxic hepatitis are discussed, together with their differentiating physiological parameters. The liver's compensatory mechanisms are examined at the level of the microcirculation. The cytokine milieu and cells responsible are considered. Survival versus cell death by means of necrosis, apoptosis, or autophagy is determined by the interplay of intracellular pathways. Specific pathways discussed involve reactive oxygen species, Toll-like receptor 4, heme oxygenase, transcription factors such as nuclear factor-κB, mitogen-activated protein kinase and protein kinase B. From this basis, current and future therapeutic strategies are examined.
This article reviews the role of neutrophils in myocardial ischemia–reperfusion injury. A number of studies have demonstrated that myocardial ischemia–reperfusion injury is an acute inflammatory process in which neutrophils are involved by accumulating at the site of ischemia injury. This process requires signals and pro-inflammatory molecules to direct neutrophils to the site of ischemia, and cell adhesion molecules to connect them with the endothelium.
Toll-like receptors (TLRs) are newly established immune receptors which are critical for host defense through the activation of both innate and adaptive immunity. TLRs can recognize molecules with both microbial and non-microbial origins. Emerging evidence now suggests that TLRs are implicated in the pathogenesis of many chronic diseases, including sepsis, atherosclerosis, ischemia/reperfusion-mediated organ dysfunction, rheumatoid arthritis, diabetes, and cancer. Therefore, an understanding of the role of TLRs in inducing chronic inflammation will provide new insights to help design an effective intervention strategy for inflammatory diseases.
The acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are part of a devastating syndrome characterized by acute onset, hypoxemia and bilateral infiltrates on chest radiography. ALI/ARDS is the response of the lung to a local or systemic insult, resulting in local inflammation and coagulation disorders, which lead to increased inflammatory pulmonary edema. ARDS is a major cause of morbidity, death, and expense in intensive care units. ALI and ARDS are associated with increased procoagulant and reduced fibrinolytic activities, mainly in alveoli and in interstitial spaces in the lung. Fibrin deposition, which is the hallmark of early-phase ALI, stimulates fibroblast aggregation and collagen secretion, participating in the constitution of pulmonary fibrosis. Despite the significant progress in the understanding of the disease made over the past 10 years, the only clinical intervention found to have a significant impact on mortality in ARDS is the use of low tidal volume ventilation. In severe sepsis, only recombinant human activated protein C administration has demonstrated a mortality reduction, together with a faster improvement in respiratory dysfunction and a shorter duration of mechanical ventilation. Future clinical trials in ALI/ARDS should evaluate the potential benefits of anticoagulants administered systemically or locally in the lungs.
Objective. To investigate the influence of traumatic brain injury (TBI) on immune function and viability of human peripheral monocytes in polytraumatized patients. Material and methods. This was a prospective, randomized, controlled clinical study conducted in a Level I trauma center. Multiply injured patients (n=42; mean age 42.4±15.5 years) with a mean Injury Severity Score (ISS) of 32.3±9.6 were compared to healthy controls (n=20; mean age 36.3±8.4 years). The methods used were clinical evaluation, scoring of injury severity (ISS, abbreviated injury scores), multiple organ dysfunction score, real-time reverse transcription polymerase chain reaction, Western blotting and fluorescent-activated cell sorting analyses of negatively isolated monocytes. The main outcome measures were overall clinical outcome, terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) staining, expression of the Fas and tumor necrosis factor receptor I, expression of the mitochondrial proteins Bax and Bcl-2, caspase-8, -9 and -3/7 activity and the level of C5a throughout a 5-day post-trauma observation period. Results. Apoptosis of peripheral blood monocytes was evident in both patient cohorts, as demonstrated by positive TUNEL staining and significant increases in caspase-3/7 activation. Trauma patients with TBI (+TBI patients) presented with a higher incidence of sepsis. Moreover, only +TBI patients demonstrated significant upregulation of pro-apoptotic mediators (increased Fas receptor) and downregulation of anti-apoptotic mediators (decreased Bcl-2) via caspase-dependent signaling (increased caspase-8 and -9) when compared to both trauma patients without TBI (−TBI patients) and healthy controls. In contrast, −TBI patients demonstrated significantly higher plasma concentrations of anaphylatoxin C5a on Day 0. Conclusions. Multiply injured patients show significant monocyte apoptosis, which may particularly promote the development of post-traumatic complications in a caspase-dependent manner in +TBI patients. The role of increased C5a and complement-associated monocyte apoptosis in −TBI patients requires further investigation.
Inflammation is the response of the body to various stimuli. Mediators of inflammation include complements, pro-coagulants, cytokines, and fibrinolytics. In renal transplantation (RT), immediately after a kidney is procured, ischemia then reperfusion (I-R) occurs, involving immunologic and non-immunologic mechanisms. Inflammation causes the generation of reactive oxygen species, lipid peroxidation, and simultaneous cell necrosis and apoptosis. The mediators of I-R injury include leukocytes, platelets, and pro-coagulants. Eventually, inflammation may cause extensive tissue destruction. Attenuation of the inflammatory process is achieved by use of an interleukin (IL)-6 antibody, zinc pretreatment, and in P-selectin knockouts. The relationship between inflammation and acute rejection (AR) is present before grafting. Pre-RT serum C-reactive protein, IL-2, and interferon (IFN)-γ concentrations before, and at 1 and 2 weeks after, RT are higher in patients who develop AR. Furthermore, renal IL-6 expression is fourfold higher in patients with AR. Administration of Met-regulated on activation, normal T cell expressed and secreted (RANTES), a chemokine receptor antagonist, suppresses recruitment of inflammatory cells into rat renal allografts. In chronic allograft nephropathy (CAN), renal lesions are induced by repeated inflammation by Th1 and/or Th2-directed antibody endothelial damage. Pro-inflammatory and pro-fibrotic mediators (IL-1, IFN-γ, tumor growth factor-β, platelet-derived growth factor, endothelin, and angiotensin II) and chemokines (RANTES) play essential roles in the development of CAN. The use of a complement regulator reduces the prevalence of CAN by minimizing I-R. Also, retinoids, which are anti-inflammatory, reduce damage consistent with CAN. In summary, there is a complex relationship between the immune system and RT organ function. Immune factors contribute to the development of organ dysfunction.
Chronic obstructive pulmonary disease (COPD) is a highly prevalent airway disorder. However, the mechanisms of the pathogenesis of COPD have not been completely elucidated to date. Transforming growth factor (TGF)-β is a pleiotropic, multifunctional cytokine participating in cell differentiation, apoptosis, survival and proliferation. TGF-β is involved in many diseases, including carcinogenesis and fibrosis. Although the most important risk factor for COPD is cigarette smoking, only 10–15% of all smokers develop the disease. This finding raises suspicion that some host or genetic factors may be involved in the pathogenesis of the disease. Thus, special attention has recently been focused on the role in COPD of TGF-β, which is active in inflammation of the airways and particularly in lung remodeling. TGF-β induces chemotaxis of mast cells and macrophages, regulates cell apoptosis and influences the protease/antiprotease balance inhibiting matrix metalloproteinase-9. TGF-β is heavily involved in repair processes. It is one of the inducers of angiogenesis, plays a role in maintaining the integrity of the pulmonary vasculature and is active in pulmonary tissue fibrosis and the development of lung emphysema. A lot of attention has been concentrated on a possible association between TGF-β1 gene polymorphism and the risk of COPD. There have been a limited number of studies on this topic, and conflicting results have been obtained. TGF-β is also considered a potential therapeutic target in COPD. Despite many attempts, these novel strategies remain in a pre-clinical phase of development and require further investigation.
Patients with severe infections and major trauma often develop multiple organ dysfunction syndrome (MODS). Aggressive fluid resuscitation can be involved in such a process and several lines of evidence have demonstrated the detrimental effects of large crystalloid-based resuscitation strategies on MODS. Additionally, fluid-restrictive strategies have been associated with a decreased frequency of acute respiratory distress syndrome (and a shorter time to recover from it) and with trends toward a shorter length of hospital stay and lower mortality. Recent knowledge of the pathophysiology of septic shock and severe trauma indicates that a release of inflammatory mediators occurs early in the course of the disease. These mediators, especially pro-inflammatory cytokines as well as hypopituitary adrenal axis dysfunction, are involved in cardiac dysfunction and vasodilatation-induced hypotension. Taking into account this combination of severe inflammation and secondary changes in endocrine profile through an earlier use of vasopressors, inotropic drugs and/or hormones may help to achieve adequate hemodynamic goals without the need for aggressive fluid resuscitation. Studies are needed to integrate these new concepts into future guidelines regarding fluid resuscitation for hypotensive patients facing sepsis or severe trauma.
Glomerulosclerosis, interstitial fibrosis, and tubular atrophy occur together with end-stage kidney failure, irrespective of the primary etiology. Transforming growth factor (TGF)-β is a key factor in these alterations either directly, by stimulating synthesis of extracellular matrix components and/or impairing turnover of extracellular matrix, or indirectly, through other profibrogenic factors such as connective tissue growth factor. TGF-β is important for the proliferation of renal interstitial fibroblasts and the epithelial–mesenchymal transition, through which tubular cells acquire fibroblastic properties. In addition, TGF-β can modulate the immune response in inflammatory renal diseases. Many humoral factors induce TGF-β expression in the kidney, chief among them being various members of the renin–angiotensin–aldosterone system. Proof of the concept that TGF-β is the main mediator of renal fibrosis stems originally from experimental and clinical observations in diabetic nephropathy, and more recently from studies of different types of glomerular disease. It has been clearly demonstrated in clinical studies that TGF-β is overproduced in the kidney and is detected in the blood and urine in various renal diseases. This review will highlight some current aspects of the TGF-β signaling axis in diabetic nephropathy and will put the topic into perspective in terms of further experimental and clinical research.
