Devin M. Boe

Extracellular traps and macrophages: new roles for the versatile phagocyte

MΦ are multipurpose phagocytes with a large repertoire of well‐characterized abilities and functions, including regulation of inflammation, wound healing, maintenance of tissue homeostasis, as well as serving as an integral component of the innate‐immune defense against microbial pathogens. Working along with neutrophils and dendritic cells, the other myeloid‐derived professional phagocytes, MΦ are one of the key effector cells initiating and directing the host reaction to pathogenic organisms and resolving subsequent responses once the threat has been cleared. ETs are a relatively novel strategy of host defense involving expulsion of nuclear material and embedded proteins from immune cells to immobilize and kill bacteria, fungi, and viruses. As research on ETs expands, it has begun to encompass many immune cell types in unexpected ways, including various types of MΦ, which are not only capable of generating METs in response to various stimuli, but recent preclinical data suggest that they are an important agent in clearing ETs and limiting ET‐mediated inflammation and tissue damage. This review aims to summarize historical and recent findings of biologic research regarding ET formation and function and discuss the role of MΦ in ET physiology and associated pathologies.

Innate immune responses in the ageing lung.

The world is undergoing an unprecedented shift in demographics, with the number of individuals over the age of 60 years projected to reach 2 billion or more by 2050, representing 22% of the global population. Elderly people are at a higher risk for chronic disease and more susceptible to infection, due in part to age‐related dysfunction of the immune system resulting from low‐grade chronic inflammation known as ‘inflamm‐ageing’. The innate immune system of older individuals exhibits a diminished ability to respond to microbial threats and clear infections, resulting in a greater occurrence of many infectious diseases in elderly people. In particular, the incidence of and mortality from lung infections increase sharply with age, with such infections often leading to worse outcomes, prolonged hospital stays and life‐threatening complications, such as sepsis or acute respiratory distress syndrome. In this review, we highlight research on bacterial pneumonias and pulmonary viral infections and discuss age‐related changes in innate immunity that contribute to the higher rate of these infections in older populations. By understanding more clearly the innate immune defects in elderly individuals, we can design age‐specific therapies to address lung infections in such a vulnerable population.

Innate Immune Responses in the Aging Lung

The world is undergoing an unprecedented shift in demographics, with the number of individuals over the age of 60 years projected to reach 2 billion or more by 2050, representing 22% of the global population. Elderly people are at a higher risk for chronic disease and more susceptible to infection, due in part to age‐related dysfunction of the immune system resulting from low‐grade chronic inflammation known as ‘inflamm‐ageing’. The innate immune system of older individuals exhibits a diminished ability to respond to microbial threats and clear infections, resulting in a greater occurrence of many infectious diseases in elderly people. In particular, the incidence of and mortality from lung infections increase sharply with age, with such infections often leading to worse outcomes, prolonged hospital stays and life‐threatening complications, such as sepsis or acute respiratory distress syndrome. In this review, we highlight research on bacterial pneumonias and pulmonary viral infections and discuss age‐related changes in innate immunity that contribute to the higher rate of these infections in older populations. By understanding more clearly the innate immune defects in elderly individuals, we can design age‐specific therapies to address lung infections in such a vulnerable population.

Ethanol intoxication prolongs post‐burn pulmonary inflammation: role of alveolar macrophages

In this study, the role and fate of AMs were examined in pulmonary inflammation after intoxication and injury. Clinical evidence has revealed that half of all burn patients brought to the emergency department are intoxicated at the time of injury. This combined insult results in amplified neutrophil accumulation and pulmonary edema, with an increased risk of lung failure and mortality, relative to either insult alone. We believe that this excessive pulmonary inflammation, which also parallels decreased lung function, is mediated in part by AMs. Restoration of lung tissue homeostasis is dependent on the eradication of neutrophils and removal of apoptotic cells, both major functions of AMs. Thirty minutes after binge ethanol intoxication, mice were anesthetized and given a 15% total body surface area dorsal scald injury. At 24 h, we found a 50% decrease in the total number of AMs (P < 0.05) and observed a proinflammatory phenotype on the remaining lung AMs. Loss of AMs paralleled a 6‐fold increase in the number of TUNEL+ lung apoptotic cells (P < 0.05) and a 3.5‐fold increase in the percentage of annexin V+ apoptotic cells in BAL (P < 0.05), after intoxication and injury, relative to controls. In contrast to the reduction in the number of cells, AMs from intoxicated and injured mice had a 4‐fold increase in efferocytosis (P < 0.05). In summary, these data suggest that loss of AMs may delay resolution of inflammation, resulting in the pulmonary complications and elevated mortality rates observed in intoxicated and burn‐injured patients.

Mesenchymal Stem Cell Treatment Attenuates Liver and Lung Inflammation after Ethanol Intoxication and Burn Injury

Cutaneous burn injury is one of the most devastating injuries one can obtain with tissue damage extending beyond the skin wound to distal organs, including the gastrointestinal tract, liver, and lungs. Multiple organ failure is a leading cause of death after burn injury resulting in excessive systemic and localized inflammation directly contributing to end organ damage. We postulated that the gut-liver-lung inflammatory axis underscores multiple organ failure in the context of burn injury and is hyper-activated when ethanol intoxication precedes burn. Mesenchymal stem cells (MSCs) are regenerative and anti-inflammatory and MSC treatment has been shown to be beneficial in several immune disorders and injury models. Our objective was to determine whether intravenous infusion of exogenous bone marrow-derived MSCs could reduce post-burn and intoxication pulmonary, hepatic, and systemic inflammation. Vehicle or ethanol (1.6 g/kg) treated mice were subjected to sham or 15% total body surface area scald burn. One hour post-injury, mice were given 5x105 CFSE-labeled MSCs or phosphate buffered saline intravenously (i.v.) and euthanized 24h later. We assessed circulating biomarkers of inflammation and liver damage, measured cytokine and chemokine production and quantified apoptosis in lung and liver tissue. Compared to intoxicated and burned mice, those treated with MSCs had less cellularity, limited apoptosis, and a slight reduction in the pro-inflammatory cytokine interleukin-6 (IL-6) and the neutrophil chemokine, KC (CXCL1) in lung tissue. MSCs treatment had more dramatic anti-inflammatory effects on systemic and hepatic inflammation, as serum IL-6 levels were diminished by 43%, il6 and kc expression in liver tissue were markedly reduced, as were biomarkers of liver damage, aspartate transaminase (AST) and alanine transaminase (AST), compared with intoxicated and burned mice. Taken together, our results suggest intravenous MSCs treatment can diminish systemic inflammation, lessen hepatic damage, and decrease liver and lung apoptosis and inflammation, indicating MSCs as a novel therapy for restoring homeostasis of multiple organ systems in intoxicated burn patients.

Age-related immune responses after burn and inhalation injury are associated with altered clinical outcomes

&NA; This prospective study aimed to address changes in inflammatory response between different aged populations of patients who sustained burn and inhalation injury. Plasma and bronchoalveolar lavage (BAL) samples were collected from 104 patients within 15 h of their estimated time of burn injury. Clinical variables, laboratory parameters, and immune mediator profiles were examined in association with clinical outcomes. Older patients were at higher odds for death after burn injury (odds ratio (OR) = 7.37 per 10 years, p = 0.004). In plasma collected within 15 h after burn injury, significant increases in the concentrations of interleukin 1 receptor antagonist (IL‐1RA), interleukin 2 (IL‐2), interleukin 4 (IL‐4), interleukin 6 (IL‐6), granulocyte colony‐stimulating factor (G‐CSF), interferon‐gamma‐induced protein 10 (IP‐10) and monocyte chemoattractant protein 1 (MCP‐1) (p < 0.05 for all) were observed in the ≥65 group. In the BAL fluid, MCP‐1 was increased three‐fold in the ≥65 group. This study suggests that changes in certain immune mediators were present in the older cohort, in association with in‐hospital mortality. HighlightsAltered inflammatory response in the older cohort when compared to younger cohort3‐Fold increase in MCP‐1 in BAL fluid samples from the elderly cohort4‐Fold, 2‐fold and 2‐fold increase of IL‐6, G‐CSF and MCP‐1 respectively in the plasma in the elderly cohortAn association between concentration of MCP‐1 in BAL fluid and in‐hospital deathIL‐1RA in the plasma fits an ROC model to be a predictor for in‐hospital death.