Disruption of pulmonary lipid homeostasis drives cigarette smoke-induced lung inflammation in mice

Morissette, Mathieu C.; Shen, Pamela; Thayaparan, Danya; Stämpfli, Martin R.

doi:10.1183/09031936.00216914

Cited by 74 publications

(76 citation statements)

References 25 publications

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“…Mouse spleen and house-dust mite exposed lung tissues were used as positive controls for CD21 and Ki67 staining, respectively. Consistent with previous reports [11,12], we showed that foamy macrophages (green arrows) were located in close proximity to the lymphoid aggregates ( Fig. 3e).…”

Section: Resultssupporting

confidence: 93%

“…However, B cell-deficient mice are completely protected from chronic smokeinduced lymphoid aggregate formation and do not develop emphysema [8]. These aggregates are often surrounded by foamy macrophages that are thought to contain cigarette smoke-induced lipid oxidation products [11] and associate with chronic inflammatory processes [12]. The role of sex and specifically female sex hormones in the pathogenesis of lymphoid follicles in small airways has not been previously investigated.…”

Section: Introductionmentioning

confidence: 99%

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Sex differences in lymphoid follicles in COPD airways

et al. 2020

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Background: Female smokers have increased risk for chronic obstructive pulmonary disease (COPD) compared with male smokers who have a similar history of cigarette smoke exposure. Tertiary lymphoid follicles are often found in the lungs of patients with severe COPD but sex-related differences have not been previously investigated. We determined the impact of female sex hormones on chronic cigarette smoke-induced expression of lymphoid aggregates in mice with COPD-like pathologies. Methods: Lymphoid aggregate counts, total aggregate cross-sectional area and foamy macrophage counts were determined morphometrically in male, female, and ovariectomized mice exposed to air or cigarette smoke for 6 months. B-cell activating factor (BAFF) protein expression and markers of oxidative stress were evaluated in mouse lung tissues by immunofluorescence staining and gene expression analyses. Quantitative histology was performed on lung tissue sections of human COPD lungs to evaluate follicle formation. Results: Lymphoid follicle and foamy macrophage counts as well as the total follicle cross-sectional area were differentially increased in lung tissues of female mice compared to male mice, and these differences were abolished by ovariectomy. These lymphoid aggregates were positive for CD45, CD20, CD21 and BAFF expression. Differential increases in Mmp12 and Cxcl2 gene expression correlated with an increase in foamy macrophages in parenchymal tissues of female but not male mice after smoke exposure. Parenchymal tissues from female mice failed to induce antioxidant-related genes in response to smoke exposure, and this effect was restored by ovariectomy. 3nitrotyrosine, a stable marker of oxidative stress, positively correlated with Mmp12 and Cxcl2 gene expression. Hydrogen peroxide induced BAFF protein in mouse macrophage cell line. In human lung tissues, female smokers with severe COPD demonstrated increased numbers of lymphoid follicles compared with males. Conclusions: Chronic smoke exposure increases the risk of lymphoid aggregate formation in female mice compared with male mice, which is mediated female sex hormones and BAFF expression in an oxidative environment.

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Section: Resultssupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Sex differences in lymphoid follicles in COPD airways

et al. 2020

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“…This is best exemplified by the rare disease pulmonary alveolar proteinosis, in which disrupted granulocyte macrophage-colony stimulating factor signaling, most commonly caused by autoantibodies, is associated with surfactant accumulation and AM immune dysfunction (14). However, the intriguing finding of increased AM "foam cells" (abnormal lipidladen AMs) in a wide range of human lung disorders (15) and rodent inhalational exposures (16,17) suggests the provocative possibility that coordinate AM dysfunction and surfactant dysregulation may play a role in a final common pathway in the pathogenesis of common chronic lung diseases and environmental exposures.…”

Section: Brief Overview Of the Unique Composition And Life Cycle Of Smentioning

confidence: 99%

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

Fessler

Summer

2016

Am J Respir Cell Mol Biol

117

111

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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.

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“…Smoking is a major risk factor for chronic obstructive pulmonary disease, interstitial lung diseases, and all types of lung cancer, especially squamous cell lung cancer. Smoking exposure rapidly leads to lipid accumulation in pulmonary macrophages, a condition associated with abnormal lung physiology, including dysregulated pulmonary innate and adaptive immune responses to the environment (8). Abnormal lipid metabolism such as increase in total and esterified cholesterol, increased fatty acid synthesis, and accumulation of lipidloaded macrophages (9)(10)(11)(12)(13) are characteristic of lung cancer.…”

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confidence: 99%

Ablation of Liver X receptors α and β leads to spontaneous peripheral squamous cell lung cancer in mice

Dai

Miao

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The etiology of peripheral squamous cell lung cancer (PSCCa) remains unknown. Here, we show that this condition spontaneously develops in mice in which the genes for two oxysterol receptors, Liver X Receptor (LXR) α (Nr1h3) and β (Nr1h2), are inactivated. By 1 y of age, most of these mice have to be euthanized because of severe dyspnea. Starting at 3 mo, the lungs of LXRα,βDko mice, but not of LXRα or LXRβ single knockout mice, progressively accumulate foam cells, so that by 1 y, the lungs are covered by a “golden coat.” There is infiltration of inflammatory cells and progressive accumulation of lipid in the alveolar wall, type 2 pneumocytes, and macrophages. By 14 mo, there are three histological lesions: one resembling adenomatous hyperplasia, one squamous metaplasia, and one squamous cell carcinoma characterized by expression of transformation-related protein (p63), sex determining region Y-box 2 (Sox2), cytokeratin 14 (CK14), and cytokeratin 13 (CK13) and absence of thyroid transcription factor 1 (TTF1), and prosurfactant protein C (pro-SPC). RNA sequencing analysis at 12 mo confirmed a massive increase in markers of M1 macrophages and lymphocytes. The data suggest a previously unidentified etiology of PSCCa: cholesterol dysregulation and M1 macrophage-predominant lung inflammation combined with damage to, and aberrant repair of, lung tissue, particularly the peripheral parenchyma. The results raise the possibility that components of the LXR signaling may be useful targets in the treatment of PSCCa.

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Disruption of pulmonary lipid homeostasis drives cigarette smoke-induced lung inflammation in mice

Cited by 74 publications

References 25 publications

Sex differences in lymphoid follicles in COPD airways

Sex differences in lymphoid follicles in COPD airways

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

Ablation of Liver X receptors α and β leads to spontaneous peripheral squamous cell lung cancer in mice

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