Surfactant Lipids at the Host-Environment Interface. Metabolic Sensors, Suppressors, and Effectors of Inflammatory Lung Disease.

The lipid composition of pulmonary surfactant is unlike that of any other body fluid. This extracellular lipid reservoir is also uniquely susceptible by virtue of its direct and continuous exposure to environmental oxidants, inflammatory agents, and pathogens. Historically, the greatest attention has been focused on those biophysical features of surfactant that serve to reduce surface tension at the air-liquid interface. More recently, surfactant lipids have also been recognized as bioactive molecules that maintain immune quiescence in the lung but can also be remodeled by the inhaled environment into neolipids that mediate key roles in inflammation, immunity, and fibrosis. This review focuses on the roles in inflammatory and infectious lung disease of two classes of native surfactant lipids, glycerophospholipids and sterols, and their corresponding oxidized species, oxidized glycerophospholipids and oxysterols. We highlight evidence that surfactant composition is sensitive to circulating lipoproteins and that the lipid milieu of the alveolus should thus be recognized as susceptible to diet and common systemic metabolic disorders. We also discuss intriguing evidence suggesting that oxidized surfactant lipids may represent an evolutionary link between immunity and tissue homeostasis that arose in the primordial lung. Taken together, the emerging picture is one in which the unique environmental susceptibility of the lung, together with its unique extracellular lipid requirements, may have made this organ both an evolutionary hub and an engine for lipid-immune cross-talk.

IL-15Rα is a determinant of muscle fuel utilization, and its loss protects against obesity.

IL-15Rα is the widely expressed primary binding partner for IL-15. Because of the wide distribution in nonlymphoid tissues like skeletal muscle, adipose, or liver, IL-15/IL-15Rα take part in physiological and metabolic processes not directly related to immunity. In fast muscle, lack of IL-15Rα promotes an oxidative switch, with increased mitochondrial biogenesis and fatigue resistance. These effects are predicted to reproduce some of the benefits of exercise and, therefore, improve energy homeostasis. However, the direct effects of IL-15Rα on metabolism and obesity are currently unknown. We report that mice lacking IL-15Rα (IL-15Rα(-/-)) are resistant to diet-induced obesity (DIO). High-fat diet-fed IL-15Rα(-/-) mice have less body and liver fat accumulation than controls. The leaner phenotype is associated with increased energy expenditure and enhanced fatty acid oxidation by muscle mitochondria. Despite being protected against DIO, IL-15Rα(-/-) are hyperglycemic and insulin-resistant. These findings identify novel roles for IL-15Rα in metabolism and obesity.

Adiponectin attenuates lipopolysaccharide-induced acute lung injury through suppression of endothelial cell activation.

Adiponectin (APN) is an adipose tissue-derived factor with anti-inflammatory and vascular protective properties whose levels paradoxically decrease with increasing body fat. In this study, APN's role in the early development of ALI to LPS was investigated. Intratracheal LPS elicited an exaggerated systemic inflammatory response in APN-deficient (APN(-/-)) mice compared with wild-type (wt) littermates. Increased lung injury and inflammation were observed in APN(-/-) mice as early as 4 h after delivery of LPS. Targeted gene expression profiling performed on immune and endothelial cells isolated from lung digests 4 h after LPS administration showed increased proinflammatory gene expression (e.g., IL-6) only in endothelial cells of APN(-/-) mice when compared with wt mice. Direct effects on lung endothelium were demonstrated by APN's ability to inhibit LPS-induced IL-6 production in primary human endothelial cells in culture. Furthermore, T-cadherin-deficient mice that have significantly reduced lung airspace APN but high serum APN levels had pulmonary inflammatory responses after intratracheal LPS that were similar to those of wt mice. These findings indicate the importance of serum APN in modulating LPS-induced ALI and suggest that conditions leading to hypoadiponectinemia (e.g., obesity) predispose to development of ALI through exaggerated inflammatory response in pulmonary vascular endothelium.

Obesity: "priming" the lung for injury.

Acute lung injury (ALI) is a severe inflammatory condition that develops in response to local and systemic lung challenges. To date, specific risk factors for development of ALI remain poorly defined. Recent epidemiological studies have reported obesity as an important predisposing factor in the development of this condition. Although the pathogenic mechanisms linking obesity and ALI have not been well-elucidated, emerging scientific evidence has described factors secreted by adipose tissue that have important biological activities in lung and has suggested that altered secretion of these factors during obesity contributes to increased ALI susceptibility. The objective of this manuscript is to highlight recent clinical evidence supporting the association between obesity and ALI and to discuss the posited role for adipose tissue-derived factors in the pathogenesis of this condition.

Adiponectin modulates inflammatory reactions via calreticulin receptor-dependent clearance of early apoptotic bodies.

Obesity and type 2 diabetes are associated with chronic inflammation. Adiponectin is an adipocyte-derived hormone with antidiabetic and antiinflammatory actions. Here, we demonstrate what we believe to be a previously undocumented activity of adiponectin, facilitating the uptake of early apoptotic cells by macrophages, an essential feature of immune system function. Adiponectin-deficient (APN-KO) mice were impaired in their ability to clear apoptotic thymocytes in response to dexamethasone treatment, and these animals displayed a reduced ability to clear early apoptotic cells that were injected into their intraperitoneal cavities. Conversely, adiponectin administration promoted the clearance of apoptotic cells by macrophages in both APN-KO and wild-type mice. Adiponectin overexpression also promoted apoptotic cell clearance and reduced features of autoimmunity in lpr mice whereas adiponectin deficiency in lpr mice led to a further reduction in apoptotic cell clearance, which was accompanied by exacerbated systemic inflammation. Adiponectin was capable of opsonizing apoptotic cells, and phagocytosis of cell corpses was mediated by the binding of adiponectin to calreticulin on the macrophage cell surface. We propose that adiponectin protects the organism from systemic inflammation by promoting the clearance of early apoptotic cells by macrophages through a receptor-dependent pathway involving calreticulin.

An Official American Thoracic Society Workshop Report: Obesity and Metabolism. An Emerging Frontier in Lung Health and Disease.

The world is in the midst of an unprecedented epidemic of obesity. This epidemic has changed the presentation and etiology of common diseases. For example, steatohepatitis, directly attributable to obesity, is now the most common cause of cirrhosis in the United States. Type 2 diabetes is increasingly being diagnosed in children. Pulmonary researchers and clinicians are just beginning to appreciate the impact of obesity and altered metabolism on common pulmonary diseases. Obesity has recently been identified as a major risk factor for the development of asthma and for acute respiratory distress syndrome. Obesity is associated with profound changes in pulmonary physiology, the development of pulmonary hypertension, sleep-disordered breathing, and altered susceptibility to pulmonary infection. In short, obesity is leading to dramatic changes in lung health and disease. Simultaneously, the rapidly developing field of metabolism, including mitochondrial function, is shifting the paradigms by which the pathophysiology of many pulmonary diseases is understood. Altered metabolism can lead to profound changes in both innate and adaptive immunity, as well as the function of structural cells. To address this emerging field, a 3-day meeting on obesity, metabolism, and lung disease was convened in October 2015 to discuss recent findings, foster research initiatives, and ultimately guide clinical care. The major findings arising from this meeting are reported in this document.

Plasma Adiponectin, clinical factors, and patient outcomes during the acute respiratory distress syndrome.

OBJECTIVE: Adiponectin (APN) is an anti-inflammatory hormone derived from adipose tissue that attenuates acute lung injury in rodents. In this study, we investigated the association between circulating APN and outcomes among patients with acute respiratory distress syndrome (ARDS). METHODS: We performed a retrospective cohort study using data and plasma samples from participants in the multicenter ARDS Network Fluid and Catheter Treatment Trial. RESULTS: Plasma APN concentrations were measured in 816 (81.6%) trial participants at baseline and in 568 (56.8%) subjects at both baseline and day 7 after enrollment. Clinical factors associated with baseline APN levels in multivariable-adjusted models included sex, body mass index, past medical history of cirrhosis, and central venous pressure (model R2 = 9.7%). We did not observe an association between baseline APN and either severity of illness (APACHE III) or extent of lung injury (Lung Injury Score). Among patients who received right heart catheterization (n = 384), baseline APN was inversely related to mean pulmonary artery pressure (ß = -0.015, R2 1.5%, p = 0.02); however, this association did not persist in multivariable models (ß = -0.009, R2 0.5%, p = 0.20). Neither baseline APN levels [HR per quartile1.04 (95% CI 0.91-1.18), p = 0.61], nor change in APN level from baseline to day 7 [HR 1.04 (95% CI 0.89-1.23), p = 0.62)] were associated with 60 day mortality in Cox proportional hazards regression models. However, subgroup analysis identified an association between APN and mortality among patients who developed ARDS from extra-pulmonary etiologies [HR per quartile 1.31 (95% CI 1.08-1.57)]. APN levels did not correlate with mortality among patients developing ARDS in association with direct pulmonary injury [HR 0.96 (95% CI 0.83-1.13)], pinteraction = 0.016. CONCLUSIONS: Plasma APN levels did not correlate with disease severity or mortality in a large cohort of patients with ARDS. However, higher APN levels were associated with increased mortality among patients developing ARDS from extra-pulmonary etiologies.

The adipokine adiponectin has potent anti-fibrotic effects mediated via adenosine monophosphate-activated protein kinase: novel target for fibrosis therapy.

INTRODUCTION: Fibrosis in scleroderma is associated with collagen deposition and myofibroblast accumulation. Peroxisome proliferator activated receptor gamma (PPAR-γ), a master regulator of adipogenesis, inhibits profibrotic responses induced by transforming growth factor-ß (TGF-ß), and its expression is impaired in scleroderma. The roles of adiponectin, a PPAR-γ regulated pleiotropic adipokine, in regulating the response of fibroblasts and in mediating the effects of PPAR-γ are unknown. METHODS: Regulation of fibrotic gene expression and TGF-ß signaling by adiponectin and adenosine monophosphate protein-activated (AMP) kinase agonists were examined in normal fibroblasts in monolayer cultures and in three-dimensional skin equivalents. AdipoR1/2 expression on skin fibroblasts was determined by real-time quantitative PCR. RESULTS: Adiponectin, an adipokine directly regulated by PPAR-γ, acts as a potent anti-fibrotic signal in normal and scleroderma fibroblasts that abrogates the stimulatory effects of diverse fibrotic stimuli and reduces elevated collagen gene expression in scleroderma fibroblasts. Adiponectin responses are mediated via AMP kinase, a fuel-sensing cellular enzyme that is necessary and sufficient for down-regulation of fibrotic genes by blocking canonical Smad signaling. Moreover, we demonstrate that endogenous adiponectin accounts, at least in part, for the anti-fibrotic effects exerted by ligands of PPAR-γ. CONCLUSIONS: These findings reveal a novel link between cellular energy metabolism and extracellular matrix homeostasis converging on AMP kinase. Since the levels of adiponectin as well as its receptor are impaired in scleroderma patients with progressive fibrosis, the present results suggest a potential role for defective adiponectin expression or function in progressive fibrogenesis in scleroderma and other chronic fibrosing conditions. Restoring the adiponectin signaling axis in fibroblasts might, therefore, represent a novel pharmacological approach to controlling fibrosis.

4. Stem and progenitor cells in the formation of the pulmonary vasculature.

The pulmonary vasculature is formed by two distinct mechanisms: vasculogenesis and angiogenesis. During vasculogenesis vessels form by de novo synthesis from cells residing within the distal mesenchyme, while in angiogenesis new vessels sprout from preexisting structures. Both processes require the activity of vascular stem/progenitor cells to differentiate and form the components of the vessel wall. In general, blood vessels are composed of two cell types, endothelial and vascular supporting cells. Isolation of these cells from the lung demonstrates remarkable heterogeneity. In part, this heterogeneity may relate to the various stem and progenitor cells involved in the formation of the pulmonary circulation. Reports indicate that multiple stem/progenitor cells, which have unique phenotypes and possess variable differentiation capacity, exist in the lung. Moreover, these cells are derived from separate tissues and contribute only to selected regions of the pulmonary circulation. In this chapter, we will summarize what is known about pulmonary vascular stem/progenitor cells, discuss their role in the development of the arterial and venous systems, and expound upon the factors limiting their study.

Stem cell antigen-1 expression in the pulmonary vascular endothelium.

Although the function of the cell surface protein stem cell antigen-1 (Sca-1) has not been identified, expression of this molecule is a characteristic of bone marrow-derived hematopoietic stem cell populations. Expression of Sca-1, however, is not restricted to hematopoietic tissue. By RT-PCR and Western analysis, we found that Sca-1 is expressed in the adult mouse lung. Sca-1 immunohistochemistry revealed a linear staining pattern on the endothelial surface of large and small pulmonary arteries and veins and alveolar capillaries. Expression of Sca-1 in the pulmonary endothelium was confirmed by dual fluorescent microscopy on lung sections and by fluorescence-activated cell sorting analysis of digested lung tissue; each of these methods showed colocalization with the endothelial marker platelet/endothelial cell adhesion molecule-1. In the kidney, Sca-1 expression was also noted in large vessels, but, in contrast to the lung, was not observed in capillaries. Overall, our data indicate that Sca-1 expression helps define the surface phenotype of endothelial cells throughout the pulmonary vasculature.