Two-pore potassium channel TREK-1 (K2P2.1) regulates NLRP3 inflammasome activity in macrophages.

Because of the importance of potassium efflux in inflammasome activation, we investigated the role of the two-pore potassium (K2P) channel TREK-1 in macrophage inflammasome activity. Using primary alveolar macrophages (AMs) and bone marrow-derived macrophages (BMDMs) from wild-type (wt) and TREK-1-/- mice, we measured responses to inflammasome priming [using lipopolysaccharide (LPS)] and activation (LPS + ATP). We measured IL-1ß, caspase-1, and NLRP3 via ELISA and Western blot. A membrane-permeable potassium indicator was used to measure potassium efflux during ATP exposure, and a fluorescence-based assay was used to assess changes in membrane potential. Inflammasome activation induced by LPS + ATP increased IL-1ß secretion in wt AMs, whereas activation was significantly reduced in TREK-1-/- AMs. Priming of BMDMs using LPS was not affected by either genetic deficiency or pharmacological inhibition of TREK-1 with Spadin. Cleavage of caspase-1 following LPS + ATP treatment was significantly reduced in TREK-1-/- BMDMs. The intracellular potassium concentration in LPS-primed wt BMDMs was significantly lower compared with TREK-1-/- BMDMs or wt BMDMs treated with Spadin. Conversely, activation of TREK-1 with BL1249 caused a decrease in intracellular potassium in wt BMDMs. Treatment of LPS-primed BMDMs with ATP caused a rapid reduction in intracellular potassium levels, with the largest change observed in TREK-1-/- BMDMs. Intracellular K+ changes were associated with changes in the plasma membrane potential (Em), as evidenced by a more depolarized Em in TREK-1-/- BMDMs compared with wt, and Em hyperpolarization upon TREK-1 channel opening with BL1249. These results suggest that TREK-1 is an important regulator of NLRP3 inflammasome activation in macrophages.NEW & NOTEWORTHY Because of the importance of potassium efflux in inflammasome activation, we investigated the role of the two-pore potassium (K2P) channel TREK-1 in macrophage inflammasome activity. Using primary alveolar macrophages and bone marrow-derived macrophages from wild-type and TREK-1-/- mice, we measured responses to inflammasome priming (using LPS) and activation (LPS + ATP). Our results suggest that TREK-1 is an important regulator of NLRP3 inflammasome activation in macrophages.

A microbial transporter of the dietary antioxidant ergothioneine.

Low-molecular-weight (LMW) thiols are small-molecule antioxidants required for the maintenance of intracellular redox homeostasis. However, many host-associated microbes, including the gastric pathogen Helicobacter pylori, unexpectedly lack LMW-thiol biosynthetic pathways. Using reactivity-guided metabolomics, we identified the unusual LMW thiol ergothioneine (EGT) in H. pylori. Dietary EGT accumulates to millimolar levels in human tissues and has been broadly implicated in mitigating disease risk. Although certain microorganisms synthesize EGT, we discovered that H. pylori acquires this LMW thiol from the host environment using a highly selective ATP-binding cassette transporter-EgtUV. EgtUV confers a competitive colonization advantage in vivo and is widely conserved in gastrointestinal microbes. Furthermore, we found that human fecal bacteria metabolize EGT, which may contribute to production of the disease-associated metabolite trimethylamine N-oxide. Collectively, our findings illustrate a previously unappreciated mechanism of microbial redox regulation in the gut and suggest that inter-kingdom competition for dietary EGT may broadly impact human health.

An infection-induced oxidation site regulates legumain processing and tumor growth.

Oxidative stress is a defining feature of most cancers, including those that stem from carcinogenic infections. Reactive oxygen species can drive tumor formation, yet the molecular oxidation events that contribute to tumorigenesis are largely unknown. Here we show that inactivation of a single, redox-sensitive cysteine in the host protease legumain, which is oxidized during infection with the gastric cancer-causing bacterium Helicobacter pylori, accelerates tumor growth. By using chemical proteomics to map cysteine reactivity in human gastric cells, we determined that H. pylori infection induces oxidation of legumain at Cys219. Legumain oxidation dysregulates intracellular legumain processing and decreases the activity of the enzyme in H. pylori-infected cells. We further show that the site-specific loss of Cys219 reactivity increases tumor growth and mortality in a xenograft model. Our findings establish a link between an infection-induced oxidation site and tumorigenesis while underscoring the importance of cysteine reactivity in tumor growth.

ASK1 Regulates Bleomycin-induced Pulmonary Fibrosis.

Pulmonary fibrosis (PF) is an abnormal remodeling of cellular composition and extracellular matrix that results in histological and functional alterations in the lungs. Apoptosis signal-regulating kinase-1 (ASK1) is a member of the mitogen-activated protein (MAP) kinase family that is activated by oxidative stress and promotes inflammation and apoptosis. Here we show that bleomycin-induced PF is reduced in Ask1 knockout mice (Ask1-/-) compared with wild-type (WT) mice, with improved survival and histological and functional parameters restored to basal levels. In WT mice, bleomycin caused activation of ASK1, p38, and extracellular signal-regulated kinase 1/2 (ERK1/2) in lung tissue, as well as changes in redox indicators (thioredoxin and heme-oxygenase-1), collagen content, and epithelial-mesenchymal transition markers (EMTs). These changes were largely restored toward untreated WT control levels in bleomycin-treated Ask1-/- mice. We further investigated whether treatment of WT mice with an ASK1 inhibitor, selonsertib (GS-4997), during the fibrotic phase would attenuate the development of PF. We found that pharmacological inhibition of ASK1 reduced activation of ASK1, p38, and ERK1/2 and promoted the restoration of redox and EMT indicators, as well as improvements in histological parameters. Our results suggest that ASK1 plays a central role in the development of bleomycin-induced PF in mice via p38 and ERK1/2 signaling. Together, these data indicate a possible therapeutic target for PF that involves an ASK1/p38/ERK1/2 axis.

SARS-CoV-2 Spike Protein Regulation of Angiotensin Converting Enzyme 2 and Tissue Renin-Angiotensin Systems: Influence of Biologic Sex.

Angiotensin converting enzyme 2 (ACE2) is an enzyme that limits activity of the renin-angiotensin system (RAS) and also serves as a receptor for the SARS-CoV-2 Spike (S) protein. Binding of S protein to ACE2 causes internalization which activates local RAS. ACE2 is on the X chromosome and its expression is regulated by sex hormones. In this study, we defined ACE2 mRNA abundance and examined effects of S protein on ACE2 activity and/or angiotensin II (AngII) levels in pivotal tissues (lung, adipose) from male and female mice. In lung, ACE2 mRNA abundance was reduced following gonadectomy (GDX) of male and female mice and was higher in XX than XY mice of the Four Core Genotypes (FCG). Reductions in lung ACE2 mRNA abundance by GDX occurred in XX, but not XY FCG female mice. Lung mRNA abundance of ADAM17 and TMPRSS2, enzymes that shed cell surface ACE2 and facilitate viral cell entry, was reduced by GDX in male but not female mice. For comparison, adipose ACE2 mRNA abundance was higher in female than male mice and higher in XX than XY FCG mice. Adipose ADAM17 mRNA abundance was increased by GDX of male and female mice. S protein reduced ACE2 activity in alveolar type II epithelial cells and 3T3-L1 adipocytes. Administration of S protein to male and female mice increased lung AngII levels and decreased adipose ACE2 activity in male but not female mice. These results demonstrate that sex differences in ACE2 expression levels may impact local RAS following S protein exposures.

Serum levels of small HDL particles are negatively correlated with death or lung transplantation in an observational study of idiopathic pulmonary fibrosis.

BACKGROUND: Serum lipoproteins, such as high-density lipoproteins (HDL), may influence disease severity in idiopathic pulmonary fibrosis (IPF). Here, we investigated associations between serum lipids and lipoproteins and clinical end-points in IPF. METHODS: Clinical data and serum lipids were analysed from a discovery cohort (59 IPF subjects, 56 healthy volunteers) and validated using an independent, multicentre cohort (207 IPF subjects) from the Pulmonary Fibrosis Foundation registry. Associations between lipids and clinical end-points (forced vital capacity, 6-min walk distance, gender age physiology (GAP) index, death or lung transplantation) were examined using Pearson's correlation and multivariable analyses. RESULTS: Serum concentrations of small HDL particles measured using nuclear magnetic resonance spectroscopy (S-HDLPNMR) correlated negatively with the GAP index in the discovery cohort of IPF subjects. The negative correlation of S-HDLPNMR with GAP index was confirmed in the validation cohort of IPF subjects. Higher levels of S-HDLPNMR were associated with lower odds of death or its competing outcome, lung transplantation (OR 0.9 for each 1-µmol·L-1 increase in S-HDLPNMR, p<0.05), at 1, 2 and 3 years from study entry in a combined cohort of all IPF subjects. CONCLUSIONS: Higher serum levels of S-HDLPNMR are negatively correlated with the GAP index, as well as with lower observed mortality or lung transplantation in IPF subjects. These findings support the hypothesis that S-HDLPNMR may modify mortality risk in patients with IPF.

Apolipoprotein E Signals via TLR4 to Induce CXCL5 Secretion by Asthmatic Airway Epithelial Cells.

The primary function of APOE (apolipoprotein E) is to mediate the transport of cholesterol- and lipid-containing lipoprotein particles into cells by receptor-mediated endocytosis. APOE also has pro- and antiinflammatory effects, which are both context and concentration dependent. For example, Apoe-/- mice exhibit enhanced airway remodeling and hyperreactivity in experimental asthma, whereas increased APOE levels in lung epithelial lining fluid induce IL-1ß secretion from human asthmatic alveolar macrophages. However, APOE-mediated airway epithelial cell inflammatory responses and signaling pathways have not been defined. Here, RNA sequencing of human asthmatic bronchial brushing cells stimulated with APOE identified increased expression of mRNA transcripts encoding multiple proinflammatory genes, including CXCL5 (C-X-C motif chemokine ligand 5), an epithelial-derived chemokine that promotes neutrophil activation and chemotaxis. We subsequently characterized the APOE signaling pathway that induces CXCL5 secretion by human asthmatic small airway epithelial cells (SAECs). Neutralizing antibodies directed against TLR4 (Toll-like receptor 4), but not TLR2, attenuated APOE-mediated CXCL5 secretion by human asthmatic SAECs. Inhibition of TAK1 (transforming growth factor-ß-activated kinase 1), IκKß (inhibitor of nuclear factor κ B kinase subunit ß), TPL2 (tumor progression locus 2), and JNK (c-Jun N-terminal kinase), but not p38 MAPK (mitogen-activated protein kinase) or MEK1/2 (MAPK kinase 1/2), attenuated APOE-mediated CXCL5 secretion. The roles of TAK1, IκKß, TPL2, and JNK in APOE-mediated CXCL5 secretion were verified by RNA interference. Furthermore, RNA interference showed that after APOE stimulation, both NF-κB p65 and TPL2 were downstream of TAK1 and IκKß, whereas JNK was downstream of TPL2. In summary, elevated levels of APOE in the airway may activate a TLR4/TAK1/IκKß/NF-κB/TPL2/JNK signaling pathway that induces CXCL5 secretion by human asthmatic SAECs. These findings identify new roles for TLR4 and TPL2 in APOE-mediated proinflammatory responses in asthma.

Apolipoprotein E is a concentration-dependent pulmonary danger signal that activates the NLRP3 inflammasome and IL-1ß secretion by bronchoalveolar fluid macrophages from asthmatic subjects.

BACKGROUND: House dust mite (HDM)-challenged Apoe-/- mice display enhanced airway hyperreactivity and mucous cell metaplasia. OBJECTIVE: We sought to characterize the pathways that induce apolipoprotein E (APOE) expression by bronchoalveolar lavage fluid (BALF) macrophages from asthmatic subjects and identify how APOE regulates IL-1ß secretion. METHODS: Macrophages were isolated from asthmatic BALF and derived from THP-1 cells and human monocytes. RESULTS: HDM-derived cysteine and serine proteases induced APOE secretion from BALF macrophages through protease-activated receptor 2. APOE at concentrations of less than 2.5 nmol/L, which are similar to levels found in epithelial lining fluid from healthy adults, did not induce IL-1ß release from BALF macrophages. In contrast, APOE at concentrations of 25 nmol/L or greater induced nucleotide-binding oligomerization domain, leucine-rich repeat-containing protein (NLRP) 3 and pro-IL-1ß expression by BALF macrophages, as well as the caspase-1-mediated generation of mature IL-1ß secreted from cells. HDM acted synergistically with APOE to both prime and activate the NLRP3 inflammasome. In a murine model of neutrophilic airway inflammation induced by HDM and polyinosinic-polycytidylic acid, APOE reached a concentration of 32 nmol/L in epithelial lining fluid, with associated increases in BALF IL-1ß levels. APOE-dependent NLRP3 inflammasome activation in macrophages was primarily mediated through a potassium efflux-dependent mechanism. CONCLUSION: APOE can function as an endogenous, concentration-dependent pulmonary danger signal that primes and activates the NLPR3 inflammasome in BALF macrophages from asthmatic subjects to secrete IL-1ß. This might represent a mechanism through which APOE amplifies pulmonary inflammatory responses when concentrations in the lung are increased to greater than normal levels, which can occur during viral exacerbations of HDM-induced asthma characterized by neutrophilic airway inflammation.

Apoptosis signal-regulating kinase-1 promotes inflammasome priming in macrophages.

We previously showed that mice deficient in apoptosis signal-regulating kinase-1 (ASK1) were partially protected against ventilator-induced lung injury. Because ASK1 can promote both cell death and inflammation, we hypothesized that ASK1 activation regulates inflammasome-mediated inflammation. Mice deficient in ASK1 expression (ASK1-/-) exhibited significantly less inflammation and lung injury (as measured by neutrophil infiltration, IL-6, and IL-1ß) in response to treatment with inhaled lipopolysaccharide (LPS) compared with wild-type (WT) mice. To determine whether this proinflammatory response was mediated by ASK1, we investigated inflammasome-mediated responses to LPS in primary macrophages and bone marrow-derived macrophages (BMDMs) from WT and ASK1-/- mice, as well as the mouse alveolar macrophage cell line MH-S. Cells were treated with LPS alone for priming or LPS followed by ATP for activation. When macrophages were stimulated with LPS followed by ATP to activate the inflammasome, we found a significant increase in secreted IL-1ß from WT cells compared with ASK1-deficient cells. LPS priming stimulated an increase in NOD-like receptor 3 (NLRP3) and pro-IL-1ß in WT BMDMs, but expression of NLRP3 was significantly decreased in ASK1-/- BMDMs. Subsequent ATP treatment stimulated an increase in cleaved caspase-1 and IL-1ß in WT BMDMs compared with ASK1-/- BMDMs. Similarly, treatment of MH-S cells with LPS + ATP caused an increase in both cleaved caspase-1 and IL-1ß that was diminished by the ASK-1 inhibitor NQDI1. These results demonstrate, for the first time, that ASK1 promotes inflammasome priming.

Low-density lipoprotein receptor-related protein 1 attenuates house dust mite-induced eosinophilic airway inflammation by suppressing dendritic cell-mediated adaptive immune responses.

BACKGROUND: Low-density lipoprotein receptor-related protein 1 (LRP-1) is a scavenger receptor that regulates adaptive immunity and inflammation. LRP-1 is not known to modulate the pathogenesis of allergic asthma. OBJECTIVE: We sought to assess whether LRP-1 expression by dendritic cells (DCs) modulates adaptive immune responses in patients with house dust mite (HDM)-induced airways disease. METHODS: LRP-1 expression on peripheral blood DCs was quantified by using flow cytometry. The role of LRP-1 in modulating HDM-induced airways disease was assessed in mice with deletion of LRP-1 in CD11c+ cells (Lrp1fl/fl; CD11c-Cre) and by adoptive transfer of HDM-pulsed CD11b+ DCs from Lrp1fl/fl; CD11c-Cre mice to wild-type (WT) mice. RESULTS: Human peripheral blood myeloid DC subsets from patients with eosinophilic asthma have lower LRP-1 expression than cells from healthy nonasthmatic subjects. Similarly, LRP-1 expression by CD11b+ lung DCs was significantly reduced in HDM-challenged WT mice. HDM-challenged Lrp1fl/fl; CD11c-Cre mice have a phenotype of increased eosinophilic airway inflammation, allergic sensitization, TH2 cytokine production, and mucous cell metaplasia. The adoptive transfer of HDM-pulsed LRP-1-deficient CD11b+ DCs into WT mice generated a similar phenotype of enhanced eosinophilic inflammation and allergic sensitization. Furthermore, CD11b+ DCs in the lungs of Lrp1fl/fl; CD11c-Cre mice have an increased ability to take up HDM antigen, whereas bone marrow-derived DCs display enhanced antigen presentation capabilities. CONCLUSION: This identifies a novel role for LRP-1 as a negative regulator of DC-mediated adaptive immune responses in the setting of HDM-induced eosinophilic airway inflammation. Furthermore, the reduced LRP-1 expression by circulating myeloid DCs in patients with eosinophilic asthma suggests a possible role for LRP-1 in modulating type 2-high asthma.

RGS4 Overexpression in Lung Attenuates Airway Hyperresponsiveness in Mice.

A cardinal feature of asthma is airway hyperresponsiveness (AHR) to spasmogens, many of which activate G protein-coupled receptors (GPCRs) on airway smooth muscle (ASM) cells. Asthma subtypes associated with allergy are characterized by eosinophilic inflammation in the lung due to the type 2 immune response to allergens and proinflammatory mediators that promote AHR. The degree to which intrinsic abnormalities of ASM contribute to this phenotype remains unknown. The regulators of G protein signaling (RGS) proteins are a large group of intracellular proteins that inhibit GPCR signaling pathways. RGS2- and RGS5-deficient mice develop AHR spontaneously. Although RGS4 is upregulated in ASM from patients with severe asthma, the effects of increased RGS4 expression on AHR in vivo are unknown. Here, we examined the impact of forced RGS4 overexpression in lung on AHR using transgenic (Tg) mice. Tg RGS4 was expressed in bronchial epithelium and ASM in vivo, and protein expression in lung was increased at least 4-fold in Tg mice compared with wild-type (WT) mice. Lung slices from Tg mice contracted less in response to the m3 muscarinic receptor agonist methacholine compared with the WT, although airway resistance in live, unchallenged mice of both strains was similar. Tg mice were partially protected against AHR induced by fungal allergen challenge due to weakened contraction signaling in ASM and reduced type 2 cytokine (IL-5 and IL-13) levels in Tg mice compared with the WT. These results provide support for the hypothesis that increasing RGS4 expression and/or function could be a viable therapeutic strategy for asthma.

Post-hypoxia Invasion of the fetal brain by multidrug resistant Staphylococcus.

Herein we describe an association between activation of inflammatory pathways following transient hypoxia and the appearance of the multidrug resistant bacteria Staphylococcus simulans in the fetal brain. Reduction of maternal arterial oxygen tension by 50% over 30 min resulted in a subseiuent significant over-expression of genes associated with immune responses 24 h later in the fetal brain. The activated genes were consistent with stimulation by bacterial lipopolysaccharide; an influx of macrophages and appearance of live bacteria were found in these fetal brains. S. simulans was the predominant bacterial species in fetal brain after hypoxia, but was found in placenta of all animals. Strains of S. simulans from the placenta and fetal brain were equally highly resistant to multiple antibiotics including methicillin and had identical genome sequences. These results suggest that bacteria from the placenta invade the fetal brain after maternal hypoxia.

High density lipoproteins and type 2 inflammatory biomarkers are negatively correlated in atopic asthmatics.

Blood eosinophil counts and serum periostin levels are biomarkers of type 2 inflammation. Although serum levels of HDL and apoA-I have been associated with less severe airflow obstruction in asthma, it is not known whether serum lipids or lipoprotein particles are correlated with type 2 inflammation in asthmatics. Here, we assessed whether serum lipids and lipoproteins correlated with blood eosinophil counts or serum periostin levels in 165 atopic asthmatics and 163 nonasthmatic subjects with and without atopy. Serum lipids and lipoproteins were quantified using standard laboratory assays and NMR spectroscopy. Absolute blood eosinophils were quantified by complete blood counts. Periostin levels were measured using the Elecsys® periostin assay. In atopic asthmatics, blood eosinophils negatively correlated with serum HDL cholesterol and total HDL particles measured by NMR spectroscopy (HDLNMR). Serum periostin levels negatively correlated with total HDLNMR In contrast, blood eosinophil counts positively correlated with serum triglyceride levels. This study demonstrates for the first time that HDL particles were negatively correlated, whereas serum triglycerides were positively correlated, with blood eosinophils in atopic asthmatics. This supports the concept that serum levels of HDL and triglycerides may be linked to systemic type 2 inflammation in atopic asthma.

High-density Lipoproteins and Apolipoprotein A-I: Potential New Players in the Prevention and Treatment of Lung Disease.

Apolipoprotein A-I (apoA-I) and high-density lipoproteins (HDL) mediate reverse cholesterol transport out of cells. Furthermore, HDL has additional protective functions, which include anti-oxidative, anti-inflammatory, anti-apoptotic, and vasoprotective effects. In contrast, HDL can become dysfunctional with a reduction in both cholesterol efflux and anti-inflammatory properties in the setting of disease or the acute phase response. These paradigms are increasingly being recognized to be active in the pulmonary system, where apoA-I and HDL have protective effects in normal lung health, as well as in a variety of disease states, including acute lung injury (ALI), asthma, chronic obstructive pulmonary disease, lung cancer, pulmonary arterial hypertension, pulmonary fibrosis, and viral pneumonia. Similar to observations in cardiovascular disease, however, HDL may become dysfunctional and contribute to disease pathogenesis in respiratory disorders. Furthermore, synthetic apoA-I mimetic peptides have been shown to have protective effects in animal models of ALI, asthma, pulmonary hypertension, and influenza pneumonia. These findings provide evidence to support the concept that apoA-I mimetic peptides might be developed into a new treatment that can either prevent or attenuate the manifestations of lung diseases, such as asthma. Thus, the lung is positioned to take a page from the cardiovascular disease playbook and utilize the protective properties of HDL and apoA-I as a novel therapeutic approach.

The A's Have It: Developing Apolipoprotein A-I Mimetic Peptides Into a Novel Treatment for Asthma.

New treatments are needed for patients with asthma who are refractory to standard therapies, such as individuals with a phenotype of "type 2-low" inflammation. This important clinical problem could potentially be addressed by the development of apolipoprotein A-I (apoA-I) mimetic peptides. ApoA-I interacts with its cellular receptor, the ATP-binding cassette subfamily A, member 1 (ABCA1), to facilitate cholesterol efflux out of cells to form nascent high-density lipoprotein particles. The ability of the apoA-I/ABCA1 pathway to promote cholesterol efflux from cells that mediate adaptive immunity, such as antigen-presenting cells, can attenuate their function. Data from experimental murine models have shown that the apoA-I/ABCA1 pathway can reduce neutrophilic airway inflammation, primarily by suppressing the production of granulocyte-colony stimulating factor. Furthermore, administration of apoA-I mimetic peptides to experimental murine models of allergic asthma has decreased both neutrophilic and eosinophilic airway inflammation, as well as airway hyperresponsiveness and mucous cell metaplasia. Higher serum levels of apoA-I have also been associated with less severe airflow obstruction in patients with asthma. Collectively, these results suggest that the apoA-I/ABCA1 pathway may have a protective effect in asthma, and support the concept of advancing inhaled apoA-I mimetic peptides to clinical trials that can assess their safety and effectiveness. Thus, we propose that the development of inhaled apoA-I mimetic peptides as a new treatment could represent a clinical advance for patients with severe asthma who are unresponsive to other therapies.

Emerging Roles of Apolipoprotein E and Apolipoprotein A-I in the Pathogenesis and Treatment of Lung Disease.

Emerging roles are being recognized increasingly for apolipoproteins in the pathogenesis and treatment of lung diseases on the basis of their ability to suppress inflammation, oxidative stress, and tissue remodeling, and to promote adaptive immunity and host defense. Apolipoproteins, such as apolipoprotein E (apoE) and apolipoprotein A-I (apoA-I), are important components of lipoprotein particles that facilitate the transport of cholesterol, triglycerides, and phospholipids between plasma and cells. ApoE-containing lipoprotein particles are internalized into cells by low-density lipoprotein receptors (LDLRs), whereas apoA-I can interact with the ATP-binding cassette subfamily A member 1 (ABCA1) transporter to efflux cholesterol and phospholipids out of cells. ApoE and apoA-I also mediate receptor-independent effects, such as binding to and neutralizing LPS. Both apoE and apoA-I are expressed by lung cells, which allows apoE/LDLR- and apoA-I/ABCA1-dependent pathways to modulate normal lung health and the pathogenesis of respiratory diseases, including asthma, acute lung injury, cancer, emphysema, pulmonary fibrosis, and pulmonary hypertension. Data from human studies and research using experimental murine model systems have shown that both apoE and apoA-I pathways play primarily protective roles in lung biology and respiratory disease. Furthermore, apolipoprotein mimetic peptides, corresponding to the LDLR-binding domain of apoE or the class A amphipathic α-helical structure of apoA-I, have antiinflammatory and antioxidant effects that attenuate the severity of lung disease in murine models. Thus, the development of inhaled apolipoprotein mimetic peptides as a novel treatment paradigm could represent a significant advance for patients with respiratory disease who do not respond to current therapies.

Serum apolipoprotein A-I and large high-density lipoprotein particles are positively correlated with FEV1 in atopic asthma.

RATIONALE: Although lipids, apolipoproteins, and lipoprotein particles are important modulators of inflammation, varying relationships exist between these parameters and asthma. OBJECTIVES: To determine whether serum lipids and apolipoproteins correlate with the severity of airflow obstruction in subjects with atopy and asthma. METHODS: Serum samples were obtained from 154 atopic and nonatopic subjects without asthma, and 159 subjects with atopy and asthma. Serum lipid and lipoprotein levels were quantified using standard diagnostic assays and nuclear magnetic resonance (NMR) spectroscopy. Airflow obstruction was assessed by FEV1% predicted. MEASUREMENTS AND MAIN RESULTS: Serum lipid levels correlated with FEV1 only in the subjects with atopy and asthma. Serum levels of high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I (apoA-I) were positively correlated with FEV1 in subjects with atopy and asthma, whereas a negative correlation existed between FEV1 and serum levels of triglycerides, low-density lipoprotein (LDL) cholesterol, apolipoprotein B (apoB), and the apoB/apoA-I ratio. NMR spectroscopy identified a positive correlation between FEV1 and HDLNMR particle size, as well as the concentrations of large HDLNMR particles and total IDLNMR (intermediate-density lipoprotein) particles in subjects with atopy and asthma. In contrast, LDLNMR particle size and concentrations of LDLNMR and VLDLNMR (very-low-density lipoprotein) particles were negatively correlated with FEV1 in subjects with atopy and asthma. CONCLUSIONS: In subjects with atopy and asthma, serum levels of apoA-I and large HDLNMR particles are positively correlated with FEV1, whereas serum triglycerides, LDL cholesterol, and apoB are associated with more severe airflow obstruction. These results may facilitate future studies to assess whether apoA-I and large HDLNMR particles can reduce airflow obstruction and disease severity in asthma.