Platelets in Inflammation and Resolution Margraf, Andreas; Zarbock, Alexander
The Journal of immunology (1950),
11/2019, Letnik:
203, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Platelets have long been known for their role in hemostasis. In this, platelet adhesion and activation leads to the formation of a firm thrombus and thus the sealing of a damaged blood vessel. More ...recently, inflammatory modes of function have been attributed to these non-nuclei-containing cellular fragments. Interaction with leukocytes, secretion of proinflammatory mediators, and migratory behavior are some of the recent discoveries. Nonetheless, platelets also have anti-inflammatory potential by regulating macrophage functions, regulatory T cells, and secretion of proresolving mediators. This review summarizes current knowledge of platelet functions with a special focus on inflammation and resolution of inflammation.
The immune system is an evolutionary hallmark of higher organisms that defends the host against invading pathogens and exogenous infections. This defense includes the recruitment of immune cells to ...the site of infection and the initiation of an inflammatory response to contain and eliminate pathogens. However, an inflammatory response may also be triggered by noninfectious stimuli such as major surgery, and, in case of an overshooting, still not comprehensively understood reaction, lead to tissue destruction and organ dysfunction. Unfortunately, in some cases, the immune system may not effectively distinguish between stimuli elicited by major surgery, which ideally should only require a modest inflammatory response, and those elicited by trauma or pathogenic infection. Surgical procedures thus represent a potential trigger for systemic inflammation that causes the secretion of proinflammatory cytokines, endothelial dysfunction, glycocalyx damage, activation of neutrophils, and ultimately tissue and multisystem organ destruction. In this review, we discuss and summarize currently available mechanistic knowledge on surgery-associated systemic inflammation, demarcation toward other inflammatory complications, and possible therapeutic options. These options depend on uncovering the underlying mechanisms and could include pharmacologic agents, remote ischemic preconditioning protocols, cytokine blockade or clearance, and optimization of surgical procedures, anesthetic regimens, and perioperative inflammatory diagnostic assessment. Currently, a large gap between basic science and clinically confirmed data exists due to a limited evidence base of translational studies. We thus summarize important steps toward the understanding of the precise time- and space-regulated processes in systemic perioperative inflammation.
Integrins are recognized as vital players in leukocyte recruitment. Integrin malfunction causes severe disease patterns characterized by the inability to fight pathogens. Although inflammatory ...reactions are beneficial and necessary for host defense, these reactions have to be controlled to prevent tissue destruction and harmful sequelae. In this review, we discuss the different signaling pathways leading to the change of integrin adhesiveness in neutrophils, monocytes, and lymphocytes. We thereby focus on the importance of integrin activation for the different steps of the leukocyte recruitment cascade, including rolling, adhesion, postadhesion strengthening, intravascular crawling, and transmigration, as each step necessitates the proper functioning of a distinct set of integrin molecules that has to be activated specifically. Additionally, we discuss endogenous mechanisms that balance and counteract integrin activation and limit leukocyte recruitment at the site of inflammation. Further insight into these complex mechanisms may provide new approaches for developing new anti-inflammatory therapies.
Acute kidney injury (AKI) is defined by a sudden loss of excretory kidney function. AKI is part of a range of conditions summarized as acute kidney diseases and disorders (AKD), in which slow ...deterioration of kidney function or persistent kidney dysfunction is associated with an irreversible loss of kidney cells and nephrons, which can lead to chronic kidney disease (CKD). New biomarkers to identify injury before function loss await clinical implementation. AKI and AKD are a global concern. In low-income and middle-income countries, infections and hypovolaemic shock are the predominant causes of AKI. In high-income countries, AKI mostly occurs in elderly patients who are in hospital, and is related to sepsis, drugs or invasive procedures. Infection and trauma-related AKI and AKD are frequent in all regions. The large spectrum of AKI implies diverse pathophysiological mechanisms. AKI management in critical care settings is challenging, including appropriate volume control, nephrotoxic drug management, and the timing and type of kidney support. Fluid and electrolyte management are essential. As AKI can be lethal, kidney replacement therapy is frequently required. AKI has a poor prognosis in critically ill patients. Long-term consequences of AKI and AKD include CKD and cardiovascular morbidity. Thus, prevention and early detection of AKI are essential.
Platelets are most often recognized for their crucial role in the control of acute hemorrhage. However, current research has greatly expanded the appreciation of platelets beyond their contribution ...to primary hemostasis, indicating that platelets also actively participate in leukocyte recruitment and the regulation of the host defense in response to exogenous pathogens and sterile injury. Early recruitment of leukocytes, especially neutrophils, is the evolutionary stronghold of the innate immune response to successfully control exogenous infections. Platelets have been shown to physically interact with different leukocyte subsets during inflammatory processes. This interaction holds far-reaching implications for the leukocyte recruitment into peripheral tissues as well as the regulation of leukocyte cell autonomous functions, including the formation and liberation of neutrophil extracellular traps. These functions critically depend on the interaction of platelets with leukocytes. The host immune response and leukocyte recruitment must be tightly regulated to avoid excessive tissue and organ damage and to avoid chronification of inflammation. Thus, platelet-leukocyte interactions and the resulting leukocyte activation and recruitment also underlies tight regulation by several inherited feedback mechanisms to limit the extend of vascular inflammation and to protect the host from collateral damage caused by overshooting immune system activation. After the acute inflammatory phase has been overcome the host defense response must eventually be terminated to allow for resolution from inflammation and restoration of tissue and organ function. Besides their essential role for leukocyte recruitment and the initiation and propagation of vascular inflammation, platelets have lately also been implicated in the resolution process. Here, their contribution to phagocyte clearance, T cell recruitment and macrophage reprogramming is also of outmost importance. This review will focus on the role of platelets in leukocyte recruitment during the initiation of the host defense and we will also discuss the participation of platelets in the resolution process after acute inflammation.
Purpose
Care bundles are recommended in patients at high risk for acute kidney injury (AKI), although they have not been proven to improve outcomes. We sought to establish the efficacy of an ...implementation of the Kidney Disease Improving Global Outcomes (KDIGO) guidelines to prevent cardiac surgery-associated AKI in high risk patients defined by renal biomarkers.
Methods
In this single-center trial, we examined the effect of a “KDIGO bundle” consisting of optimization of volume status and hemodynamics, avoidance of nephrotoxic drugs, and preventing hyperglycemia in high risk patients defined as urinary TIMP-2·IGFBP7 > 0.3 undergoing cardiac surgery. The primary endpoint was the rate of AKI defined by KDIGO criteria within the first 72 h after surgery. Secondary endpoints included AKI severity, need for dialysis, length of stay, and major adverse kidney events (MAKE) at days 30, 60, and 90.
Results
AKI was significantly reduced with the intervention compared to controls 55.1 vs. 71.7%; ARR 16.6% (95 CI 5.5–27.9%);
p
=
0.004. The implementation of the bundle resulted in significantly improved hemodynamic parameters at different time points (
p
< 0.05), less hyperglycemia (
p
< 0.001) and use of ACEi/ARBs (
p
< 0.001) compared to controls. Rates of moderate to severe AKI were also significantly reduced by the intervention compared to controls. There were no significant effects on other secondary outcomes.
Conclusion
An implementation of the KDIGO guidelines compared with standard care reduced the frequency and severity of AKI after cardiac surgery in high risk patients. Adequately powered multicenter trials are warranted to examine mortality and long-term renal outcomes.
Platelets participate in many important physiological processes, including hemostasis and immunity. However, despite their broad participation in these evolutionarily critical roles, the anucleate ...platelet is uniquely mammalian. In contrast with the large nucleated equivalents in lower vertebrates, we find that the design template for the evolutionary specialization of platelets shares remarkable similarities with human-engineered unmanned aerial vehicles in terms of overall autonomy, maneuverability, and expendability. Here, we review evidence illustrating how platelets are uniquely suited for surveillance and the manner in which they consequently provide various types of support to other cell types.
Surgery and other invasive procedures, which are routinely performed during general anesthesia, may induce an inflammatory response in the patient. This inflammatory response is an inherent answer of ...the body to the intervention and can be both beneficial and potentially harmful. The immune system represents a unique evolutionary achievement equipping higher organisms with an effective defense mechanism against exogenous pathogens. However, not only bacteria might evoke an immune response but also other noninfectious stimuli like the surgical trauma or mechanical ventilation may induce an inflammatory response of varying degree. In these cases, the immune system activation is not always beneficial for the patients and might carry the risk of concomitant, harmful effects on host cells, tissues, or even whole organ systems. Research over the past decades has contributed substantial information in which ways surgical patients may be affected by inflammatory reactions. Modulations of the patient’s immune system may be evoked by the use of anesthetic agents, the nature of surgical trauma and the use of any supportive therapy during the perioperative period. The effects on the patient may be manifold, including various proinflammatory effects. This review focuses on the causes and effects of inflammation in the perioperative period. In addition, we also highlight possible approaches by which inflammation in the perioperative may be modulated in the future.
Sepsis is a severe critical illness syndrome that arises from infectious insults. While the host immune system is generally beneficial, an overshooting and unregulated immune response can cause ...serious organ tissue injury. During sepsis, systemic hypotension, disturbed perfusion of the microcirculation, and direct tissue-toxicity caused by inflammatory immune reaction can occur and contribute to organ failure. The failure of two or more vital organ systems is termed multi-organ dysfunction syndrome (MODS) and resembles a very critical condition associated with high morbidity and mortality. Importantly, no specific treatment strategy exists to efficiently prevent the development of MODS during sepsis. In this review, we aim to identify the relevant molecular immunological pathways involved in the pathogenesis of MODS during sepsis. We believe that a detailed understanding of this mechanism is necessary for the development of new treatment approaches for septic patients. In particular, knowledge of the endogenous regulators keeping the balance between necessary immune system activation to combat infections and prevention of host tissue damage would greatly improve the chances for the development of effective interventions.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). Understanding of the fundamental processes underlying the versatile ...clinical manifestations of COVID-19 is incomplete without comprehension of how different immune cells are recruited to various compartments of virus-infected lungs, and how this recruitment differs among individuals with different levels of disease severity. As in other respiratory infections, leukocyte recruitment to the respiratory system in people with COVID-19 is orchestrated by specific leukocyte trafficking molecules, and when uncontrolled and excessive it results in various pathological complications, both in the lungs and in other organs. In the absence of experimental data from physiologically relevant animal models, our knowledge of the trafficking signals displayed by distinct vascular beds and epithelial cell layers in response to infection by SARS-CoV-2 is still incomplete. However, SARS-CoV-2 and influenza virus elicit partially conserved inflammatory responses in the different respiratory epithelial cells encountered early in infection and may trigger partially overlapping combinations of trafficking signals in nearby blood vessels. Here, we review the molecular signals orchestrating leukocyte trafficking to airway and lung compartments during primary pneumotropic influenza virus infections and discuss potential similarities to distinct courses of primary SARS-CoV-2 infections. We also discuss how an imbalance in vascular activation by leukocytes outside the airways and lungs may contribute to extrapulmonary inflammatory complications in subsets of patients with COVID-19. These multiple molecular pathways are potential targets for therapeutic interventions in patients with severe COVID-19.
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