Geoffrey Bellingan

Effects of Low-Dose Aspirin on Acute Inflammatory Responses in Humans

Aspirin is a unique nonsteroidal anti-inflammatory drug; at high doses (aspirinhigh, 1g), it is anti-inflammatory stemming from the inhibition of cyclooxygenase and proinflammatory signaling pathways including NF-κB, but is cardioprotective at lower doses (aspirinlow, 75 mg). The latter arises from the inhibition of thromboxane (Tx) B2, a prothrombotic eicosanoid also implicated in polymorphonuclear leukocyte trafficking. As a result, aspirinlow is widely used as a primary and secondary preventative against vascular disease. Despite this and its ability to synthesize proresolution 15-epi-lipoxin A4 it is not known whether aspirinlow is anti-inflammatory in humans. To address this, we generated skin blisters by topically applying cantharidin on the forearm of healthy male volunteers, causing an acute inflammatory response including dermal edema formation and leukocyte trafficking. Although not affecting blister fluid volume, aspirinlow (75 mg, oral, once daily/10 days) reduced polymorphonuclear leukocyte and macrophage accumulation independent of NF-κB-regulated gene expression and inhibition of conventional prostanoids. However, aspirinlow triggered 15-epi-lipoxin A4 synthesis and up-regulated its receptor (FPRL1, ALX). From complimentary in vitro experiments, we propose that 15-epi-lipoxin A4 exerts its protective effects by triggering antiadhesive NO, thereby dampening leukocyte/endothelial cell interaction and subsequent extravascular leukocyte migration. Since similar findings were obtained from murine zymosan-induced peritonitis, we suggest that aspirinlow possesses the ability to inhibit mammalian innate immune-mediated responses. This highlights 15-epi-lipoxin A4 as a novel anti-inflammatory working through a defined receptor and suggests that mimicking its mode of action represents a new approach to treating inflammation-driven diseases.

Targeted temperature management in critical care: A report and recommendations from five professional societies*

Objective:Representatives of five international critical care societies convened topic specialists and a nonexpert jury to review, assess, and report on studies of targeted temperature management and to provide clinical recommendations. Data Sources:Questions were allocated to experts who reviewed their areas, made formal presentations, and responded to questions. Jurors also performed independent searches. Sources used for consensus derived exclusively from peer-reviewed reports of human and animal studies. Study Selection:Question-specific studies were selected from literature searches; jurors independently determined the relevance of each study included in the synthesis. Conclusions and Recommendations:1) The jury opines that the term “targeted temperature management” replace “therapeutic hypothermia.” 2) The jury opines that descriptors (e.g., “mild”) be replaced with explicit targeted temperature management profiles. 3) The jury opines that each report of a targeted temperature management trial enumerate the physiologic effects anticipated by the investigators and actually observed and/or measured in subjects in each arm of the trial as a strategy for increasing knowledge of the dose/duration/response characteristics of temperature management. This enumeration should be kept separate from the body of the report, be organized by body systems, and be made without assertions about the impact of any specific effect on the clinical outcome. 4) The jury STRONGLY RECOMMENDS targeted temperature management to a target of 32°C–34°C as the preferred treatment (vs. unstructured temperature management) of out-of-hospital adult cardiac arrest victims with a first registered electrocardiography rhythm of ventricular fibrillation or pulseless ventricular tachycardia and still unconscious after restoration of spontaneous circulation (strong recommendation, moderate quality of evidence). 5) The jury WEAKLY RECOMMENDS the use of targeted temperature management to 33°C–35.5°C (vs. less structured management) in the treatment of term newborns who sustained asphyxia and exhibit acidosis and/or encephalopathy (weak recommendation, moderate quality of evidence).

Severity of Lung Injury in Cyclooxygenase-2- Deficient Mice Is Dependent on Reduced Prostaglandin E 2 Production

Levels of prostaglandin E(2) (PGE(2)), a potent inhibitor of fibroblast function, are decreased in the lungs of patients with pulmonary fibrosis, which has been shown to be because of limited expression of cyclooxygenase-2 (COX-2). To further investigate the relative importance of COX-2 and PGE(2) in the development of fibrosis we have used a selective COX-2 inhibitor and COX-2-deficient ((-/-) and (+/-)) mice in studies of bleomycin-induced lung fibrosis. We demonstrate in wild-type mice that bleomycin-induced lung PGE(2) production is predominantly COX-2 mediated. Furthermore, COX-2(+/-) mice show limited induction of PGE(2) and an enhanced fibrotic response with increased lung collagen content compared with wild-type mice after bleomycin injury (P < 0.001). In contrast, COX-2(-/-) mice show increased levels of lung PGE(2), compared with wild-type mice after injury (P < 0.05), because of compensatory up-regulation of COX-1, which appears to be associated with macrophage/monocytes but not fibroblasts derived from these mice. COX-2(-/-) mice show an enhanced and persistent inflammatory response to bleomycin, however the fibrotic response to injury was unaltered compared with wild-type animals. These data provide further direct evidence for the importance of up-regulating COX-2 and PGE(2) expression in protecting against the development of fibrosis after lung injury.

Dichotomy in duration and severity of acute inflammatory responses in humans arising from differentially expressed proresolution pathways

Lipoxins (Lxs) and aspirin-triggered epi-Lxs (15-epi-LxA4) act through the ALX/FPRL1 receptor to block leukocyte trafficking, dampen cytokine/chemokine synthesis, and enhance phagocytic clearance of apoptotic leukocytes—key requisites for inflammatory resolution. Although studies using primarily inbred rodents have highlighted resolution as an active event, little is known about the role resolution pathways play in controlling the duration/profile of inflammatory responses in humans. To examine this, we found two types of responders to cantharidin-induced skin blisters in male healthy volunteers: those with immediate leukocyte accumulation and cytokine/chemokine synthesis followed by early resolution and a second group whose inflammation increased gradually over time followed by delayed resolution. In early resolvers, blister 15-epi-LxA4 and leukocyte ALX were low, but increased as inflammation abated. In contrast, in delayed resolvers, 15-epi-LxA4 and ALX were high early in the response but waned as inflammation progressed. Elevating 15-epi-LxA4 in early resolvers using aspirin increased blister leukocyte ALX but reduced cytokines/chemokines as well as polymorphonuclear leukocyte and macrophage numbers. These findings show that two phenotypes exist in humans with respect to inflammation severity/longevity controlled by proresolution mediators, namely 15-epi-LxA4. These data have implications for understanding the etiology of chronic inflammation and future directions in antiinflammatory therapy.

The acute respiratory distress syndrome: fibrosis in the fast lane

The acute respiratory distress syndrome (ARDS) is an acute and severe form of microvascular lung injury which is frequently seen in intensive therapy units. Reductions in mortality have been reported by some centres; however, 40–70% of patients still die from this syndrome.1 2 Treatment at present is largely supportive and, despite our increased understanding of the pathological processes involved, there are no specific treatments of proven benefit. Interstitial and intra-alveolar fibrosis are hallmarks of the more advanced stages of ARDS and are characterised by the abnormal and excessive deposition of extracellular matrix proteins, in particular collagen.3 4 Histologically and biochemically this is similar to the fibrosis seen in other more chronic forms of interstitial lung disease4; however, more is known of the mediators and cellular events that occur in these disorders. The decrease in pulmonary compliance and progressive hypoxia resulting from fibrotic change leads to ventilator dependence. As a result, progressive fibrosis is a direct cause of respiratory death in up to 40% of patients3 5 but is also an indirect cause of death due to nosocomial infection and progressive multi-organ failure in up to 70% of patients who die from ARDS.6 Thus, the fibrotic process is an important determinant of outcome and a potential target for therapeutic intervention. ARDS is traditionally divided into three phases: exudative, proliferative and fibrotic (fig 1). The initial exudative phase involves the leakage of proteinaceous fluid and the migration of cells, in particular neutrophils, from the circulation into the interstitium and alveolar space following diffuse damage to the endothelial and epithelial surfaces. The proliferation of fibroblasts and type II pneumocytes characterises the second phase during which activated fibroblasts secrete a number of extracellular matrix proteins within the interstitium but also migrate into the alveolar space where they form …

Importance of the environment for patient acquisition of methicillin-resistant Staphylococcus aureus in the intensive care unit : A baseline study

Objective:To assess the degree of environmental contamination with methicillin-resistant Staphylococcus aureus (MRSA) in critical care and the likelihood of subsequent new patient acquisition if carriers were or were not moved to single rooms. Design:Randomized sequential sampling of bed areas. Setting:Intensive care units of two teaching hospitals. Patients:Medical and surgical patients requiring critical care. Interventions:Six environmental sites around randomly selected patients plus two communal sites were sampled using contact plates during periods when patients with MRSA were physically isolated or not. Admission, weekly, and discharge screening patient swabs were taken to identify patients admitted with, or newly acquiring, MRSA. Measurements and Main Results:A total of 2,436 samples were taken from environments around 114 patients, plus a further 349 samples from doctors’ hands and telephones. Of the 47 bed areas where MRSA strains were identified that were not found initially on patients, only one patient subsequently acquired the same strain. Five other patients became colonized with new MRSA strains, but these were not found in their environment beforehand. Of 52 patients colonized with MRSA, 34 had a similar strain found subsequently in their environment. Conclusions:Whereas the MRSA-colonized patient frequently contaminates his or her local environment, transmission of MRSA from the environment to the patient was not commonly identified. Studies elucidating possible routes of MRSA transmission are urgently needed to inform infection control policies.

Fate of macrophages once having ingested apoptotic cells: Lymphatic clearance or in situ apoptosis?

Neutrophil and macrophage kinetics at the inflamed site differ markedly [1, 2]. Unlike neutrophils, many organs and tissues have a population of resident macrophages, hence these cells have a different baseline at the outset of inflammation. Resident macrophages are a key population in the initiation of local inflammation [3]. Neutrophils influx rapidly early in the acute inflammatory event, while resident tissue macrophages may actually decline in numbers due to a process known as the macrophage disappearance reaction (MDR) [4]. Like neutrophils, inflammatory monocytes migrate in from the blood stream, although this lags somewhat behind the insurgence of neutrophils. These monocytes mature locally into inflammatory macrophages, although their activation state may alter over the course of the inflammatory process [5, 6]. Neutrophil numbers peak earlier than macrophages. Their decline can be due to necrosis, apoptosis and subsequent phagocytosis, or progressing to secondary necrosis if phagocytosis of apoptotic cells fails [7]. Neutrophils may be able to efflux away from the inflamed site, for example back into the blood stream, or, with pulmonary inflammation for example, they can migrate into the airway lumen [8]–[10]. It appears, however, that their main fate is to undergo apoptosis locally as shown in a number of models and in vivo settings [7, 11]. In normally resolving inflammation, macrophages phagocytose the apoptotic neutrophils and their numbers then decline allowing the tissue to return to normal structure and function [12]–[14]. This chapter examines macrophage clearance in the resolution of inflammation.

Acute Lung Injury and Acute Respiratory Distress Syndrome (ALI/ARDS)

Acute Lung Injury/Acute Respiratory Distress Syndrome (ALI/ARDS) is one of the most devastating conditions that critically ill patients de-velop. Major advances in understanding the patho-genesis of ALI/ARDS have been made since its initial description in the 1960s. However, the mortality rate for the condition remains high and, to date, there remains no pharmacological therapy that has had an unequivocal benefit in clinical trials.