Lung Immune Tone Regulation by the Gut-Lung Immune Axis: Short-chain Fatty Acid Receptors FFAR2 and FFAR3, and IL-1β Expression Profiling in Mouse and Human Lung

ABSTRACTMicrobial metabolites produced by the gut microbiome, such as short-chain fatty acids (SCFA), can influence both local intestinal and distant lung physiology and response to injury. However, how lung immune activity is regulated by SCFAs is unknown. We examined fresh human lung tissue and observed the presence of SCFAs with large inter-individual and even intra-lobe variability. In vitro, SCFAs were capable of modifying the metabolic programming in both resting and LPS-exposed alveolar macrophages (AM). Additionally, since we hypothesized that lung immune tone could be defined through priming of the inflammasome (aka signal 1), we interrogated naïve mouse lungs for pro-IL-1β message and localized its presence within the alveolar space in situ, specifically in AM subsets, and in close proximity to alveolar type 2 epithelial (AT2) cells. We established that metabolically active gut microbiota, that produce SCFAs, can transmit LPS and SCFAs to the lung (potential sources of signal 1), and thereby could regulate lung immune tone and metabolic programming. To understand how murine lung cells sensed and upregulated IL-1β in response to gut-microbiome factors, we determined that in vitro, AM and AT2 cells expressed SCFA receptors, FFAR2, FFAR3, and IL-1β but with different expression patterns and LPS-inducibility. Finally, we observed that IL-1β, FFAR2 and FFAR3 were expressed both in isolated human AM and AT2 cells ex-vivo, but in fresh human lung sections in situ, only AM expressed IL-1β at rest and after LPS challenge. Together, this translational study using mouse and human lung tissue and cells supports an important role for the gut microbiome and SCFAs in regulating lung immune tone.

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Lung Immune Tone via Gut-Lung Axis: Gut-derived LPS and Short-chain Fatty Acids' immunometabolic regulation of Lung IL-1β, FFAR2 and FFAR3 Expression

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00421.2020 ◽

2021 ◽

Author(s):

Qing Liu ◽

Xiaoli Tian ◽

Daisuke Maruyama ◽

Mehrdad Arjomandi ◽

Arun Prakash

Keyword(s):

Fatty Acids ◽

Gut Microbiota ◽

Lung Tissue ◽

Gut Microbiome ◽

Human Lung ◽

Short Chain Fatty Acids ◽

Short Chain ◽

Human Lung Tissue ◽

Chain Fatty Acids

Microbial metabolites produced by the gut microbiome, e.g. short-chain fatty acids (SCFA), have been found to influence lung physiology and injury responses. However, how lung immune activity is regulated by SCFA is unknown. We examined fresh human lung tissue and observed the presence of SCFA with inter-individual variability. In vitro, SCFA were capable of modifying the metabolic programming in LPS-exposed alveolar macrophages (AM). We hypothesized that lung immune tone could be defined by baseline detection of lung intracellular IL-1β. Therefore, we interrogated naïve mouse lungs with intact gut microbiota for IL-1β mRNA expression and localized its presence within alveolar spaces, specifically within AM subsets. We established that metabolically active gut microbiota, that produce SCFA, can transmit LPS and SCFA to the lung and thereby could create primed lung immunometabolic tone. To understand how murine lung cells sensed and upregulated IL-1β in response to gut microbiome-derived factors, we determined that, in vitro, AM and AT2 cells expressed SCFA receptors, FFAR2, FFAR3, and IL-1β but with distinct expression patterns and different responses to LPS. Finally, we observed that IL-1β, FFAR2 and FFAR3 were expressed in isolated human AM and AT2 cells ex-vivo, but in fresh human lung sections in situ, only AM expressed IL-1β at rest and after LPS challenge. Together, this translational study using mouse and human lung tissue and cells point to an important role for the gut microbiome and their SCFA in establishing and regulating lung immune tone.

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A labelled-ubiquicidin antimicrobial peptide for immediate in situ optical detection of live bacteria in human alveolar lung tissue

Chemical Science ◽

10.1039/c5sc00960j ◽

2015 ◽

Vol 6 (12) ◽

pp. 6971-6979 ◽

Cited By ~ 50

Author(s):

Ahsan R. Akram ◽

Nicolaos Avlonitis ◽

Annamaria Lilienkampf ◽

Ana M. Perez-Lopez ◽

Neil McDonald ◽

...

Keyword(s):

Antimicrobial Peptide ◽

Lung Tissue ◽

Human Lung ◽

Optical Detection ◽

Human Lung Tissue ◽

Bacterial Detection ◽

Live Bacteria

A fluorescently labelled ubiquicidin peptide enables bacterial detection in human lung tissuein vitro.

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The Glucocorticosteroid, Budesonide, Partially Blocks Histamine Release from Human Lung Tissue in Vitro

Allergy ◽

10.1111/j.1398-9995.1986.tb00307.x ◽

1986 ◽

Vol 41 (5) ◽

pp. 319-326 ◽

Cited By ~ 6

Author(s):

H. Bergstrand ◽

B. Lundquist ◽

B.-Å. Petersson

Keyword(s):

Histamine Release ◽

Lung Tissue ◽

Human Lung ◽

Human Lung Tissue

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Light distribution in human lung tissue at 413.1 nm in vitro

10.1117/12.297878 ◽

1998 ◽

Cited By ~ 1

Author(s):

Zhiwei Huang ◽

Chee T. Chia ◽

Cheong Hoong Diong ◽

Sing Lee ◽

Wei-Ming Zheng ◽

...

Keyword(s):

Lung Tissue ◽

Human Lung ◽

Light Distribution ◽

Human Lung Tissue

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High-Resolution CT Findings of Leukemia Pulmonary Infiltration and Chemotherapy Outcome and In Vitro Study of Human Lung Tissue

Journal of Medical Imaging and Health Informatics ◽

10.1166/jmihi.2021.3276 ◽

2021 ◽

Vol 11 (2) ◽

pp. 360-369

Author(s):

Caide Xie ◽

Tianjing Zhao ◽

Liang Fang

Keyword(s):

High Resolution ◽

Lung Tissue ◽

Human Lung ◽

Ct Imaging ◽

Imaging Features ◽

Human Lung Tissue ◽

High Resolution Ct ◽

Ct Findings ◽

Pulmonary Infiltration

In order to explore the high-resolution CT findings of leukemia pulmonary infiltration and chemotherapy outcomes and the in vitro study of human lung tissue, this paper selected a total of 120 clinically or surgically confirmed leukemia patients at the designated hospital of the study from December 2014 to December 2018, and divided them into three groups according to the random number table method: pulmonary infiltration group, chemotherapy outcome group and in vitro study group, with 40 cases in each group. The CT imaging features of the three groups of patients were observed and summarized respectively; the anomalous evaluation indexes of pulmonary parenchyma tissue abnormalities included CT halo sign, air crescent sign, lung segment consolidation, bronchial vascular bundle and nodules; the CT abnormalities such as thickening of the interlobular septum, bronchial interstitial thickening, nodular shadow, ground glassy change, and air cavity consolidation were selected as observation indicators. The results show that all cases have multiple solid nodules or multiple plaques, varying in number, size and distribution, in which 13 cases have multiple patchy shadows, 9 cases have multiple knots and 11 cases have multiple plaques and nodules; lesions are mainly distributed along the bronchial vessels in 21 cases, and 9 cases are along the center of the small leaves and 5 cases are randomly distributed; there are 13 cases that have frosted glass, in which 4 cases with pleural effusion, 9 cases with mold infection, show multiple patchy shadows with halo signs and layered mold balls. In summary, leukemia pulmonary infiltration has polymorphic high-resolution CT findings and chemotherapy outcomes; high-resolution CT imaging and in vitro studies of human lung tissue have important clinical and pathological research value for leukemia infiltration and chemotherapy outcome. The results of this study provide a reference for the further researches on high-resolution CT findings of pulmonary infiltration and chemotherapy outcomes and in vitro studies of human lung tissue.

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Novel Human Lung Tissue Model for the Study of SARS-CoV-2 Entry, Inflammation and New Therapeutics

10.1101/2021.04.21.440731 ◽

2021 ◽

Author(s):

Judith Grau-Expósito ◽

David Perea ◽

Marina Suppi ◽

Núria Massana ◽

Ander Vergara ◽

...

Keyword(s):

Lung Tissue ◽

Viral Entry ◽

Human Lung ◽

Inflammatory Responses ◽

Alveolar Type ◽

List Type ◽

Human Lung Tissue ◽

Main Cell ◽

Anti Inflammatory ◽

Conventional Systems

AbstractThe development of physiological models that reproduce SARS-CoV-2 infection in primary human cells will be instrumental to identify host-pathogen interactions and potential therapeutics. Here, using cell suspensions from primary human lung tissues (HLT), we have developed a platform for the identification of viral targets and the expression of viral entry factors, as well as for the screening of viral entry inhibitors and anti-inflammatory compounds. We show that the HLT model preserves its main cell populations, maintains the expression of proteins required for SARS-CoV-2 infection, and identifies alveolar type II (AT-II) cells as the most susceptible cell targets for SARS-CoV-2 in the human lung. Antiviral testing of 39 drug candidates revealed a highly reproducible system, and provided the identification of new compounds missed by conventional systems such as VeroE6. Using this model, we also show that interferons do not modulate ACE2 expression, and that stimulation of local inflammatory responses can be modulated by different compounds with antiviral activity. Overall, we present a novel and relevant physiological model for the study of SARS-CoV-2.SynopsisEx vivo physiological systems for the study of SARS-CoV-2-host interactions are scarce. Here, we establish a novel model using primary human lung tissue (HLT) for the analysis of cell tropism and identification of therapeutics.The HLT model preserves main cell subpopulations, including alveolar type-2 cells, and expression of SARS-CoV-2 entry factors ACE2, CD147, and TMPRSS2.The HLT model is readily susceptible to SARS-CoV-2 entry.Antiviral testing in the HLT model allows the identification of new candidates missed by conventional systems.Local inflammation is supported in the HLT model and offers the identification of relevant anti-inflammatory compounds for SARS-CoV-2 infection.

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Electron microscopic study of human lung tissue after in vitro exposure to elastase.

Journal of Histochemistry & Cytochemistry ◽

10.1177/41.6.8315277 ◽

1993 ◽

Vol 41 (6) ◽

pp. 851-866 ◽

Cited By ~ 5

Author(s):

S M Morris ◽

P J Stone ◽

G L Snider

Keyword(s):

Animal Models ◽

Lung Tissue ◽

Human Lung ◽

Basement Membranes ◽

Morphological Evidence ◽

Elastic Fibers ◽

Human Neutrophil Elastase ◽

Human Lung Tissue ◽

Thin Sections

Much of the experimental evidence supporting the hypothesis that pulmonary emphysema results from an imbalance between elastases and anti-elastases in the lung comes from animal models. The present study was designed to examine the effects on human lung tissue of the two elastases that have been most widely used to produce these animal models. Lung tissue was exposed in vitro to human neutrophil elastase (HNE) or porcine pancreatic elastase (PPE). Although both enzymes solubilized protein at similar rates, PPE solubilized elastin five times faster than did HNE. Ultrastructurally, HNE-exposed tissue exhibited fewer damaged elastic fibers as well as some fibers that were damaged at the edges, whereas the interior of the fiber appeared intact. Elastic fibers showing damage only at the periphery were not seen in tissue exposed to PPE. Immunocytochemical studies in which antibodies to HNE and PPE were applied to thin sections of Lowicryl-embedded tissue indicated that both of these elastases could be detected in association with elastic fibers, but only in areas of the fiber that showed morphological evidence of elastase injury. Both HNE and PPE removed fibronectin from basement membranes (as determined by loss of binding of fibronectin antibodies after exposure to elastase), but neither elastase was detected on basement membrane. Loss of epithelial cells usually accompanied elastic fiber damage by HNE but not PPE.

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Development of anEx VivoTissue Platform To Study the Human Lung Response to Coxiella burnetii

Infection and Immunity ◽

10.1128/iai.00012-16 ◽

2016 ◽

Vol 84 (5) ◽

pp. 1438-1445 ◽

Cited By ~ 12

Author(s):

Joseph G. Graham ◽

Caylin G. Winchell ◽

Richard C. Kurten ◽

Daniel E. Voth

Keyword(s):

Coxiella Burnetii ◽

Lung Tissue ◽

Human Lung ◽

Q Fever ◽

Ex Vivo ◽

Parasitophorous Vacuole ◽

Inflammasome Activation ◽

Human Lung Tissue ◽

Content Type

Coxiella burnetiiis an intracellular bacterial pathogen that causes human Q fever, an acute debilitating flu-like illness that can also present as chronic endocarditis. Disease typically occurs following inhalation of contaminated aerosols, resulting in an initial pulmonary infection. In human cells,C. burnetiigenerates a replication niche termed the parasitophorous vacuole (PV) by directing fusion with autophagosomes and lysosomes.C. burnetiirequires this lysosomal environment for replication and uses a Dot/Icm type IV secretion system to generate the large PV. However, we do not understand howC. burnetiievades the intracellular immune surveillance that triggers an inflammatory response. We recently characterized human alveolar macrophage (hAM) infectionin vitroand found that avirulentC. burnetiitriggers sustained interleukin-1β (IL-1β) production. Here, we evaluated infection ofex vivohuman lung tissue, defining a valuable approach for characterizingC. burnetiiinteractions with a human host. Within whole lung tissue,C. burnetiipreferentially replicated in hAMs. Additionally, IL-1β production correlated with formation of an apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC)-dependent inflammasome in response to infection. We also assessed potential activation of a human-specific noncanonical inflammasome and found that caspase-4 and caspase-5 are processed during infection. Interestingly, although inflammasome activation is closely linked to pyroptosis, lytic cell death did not occur followingC. burnetii-triggered inflammasome activation, indicating an atypical response after intracellular detection. Together, these studies provide a novel platform for studying the human innate immune response toC. burnetii.

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Effect of Benoxaprofen on Release of Slow-Reacting Substances from Human Lung Tissue In Vitro

Clinical Science ◽

10.1042/cs0630219 ◽

1982 ◽

Vol 63 (2) ◽

pp. 219-221 ◽

Cited By ~ 5

Author(s):

V. Y. Lee ◽

J. Margaret Hughes ◽

J. P. Seale ◽

Diana M. Temple

Keyword(s):

Lung Cancer ◽

Lung Tissue ◽

Human Lung ◽

Calcium Ionophore ◽

Inhibitory Effects ◽

Human Lung Tissue ◽

Normal Human ◽

Clinical Asthma

1. Macroscopically normal human lung tissue was obtained from operative specimens removed for lung cancer and challenged with antigen or calcium ionophore. The release of histamine and slow-reacting substances was measured by fluorimetric and bioassay techniques respectively. 2. Benoxaprofen, a drug with inhibitory effects on the lipoxygenase and cyclo-oxygenase pathways, caused a dose-related reduction of release of slow-reacting substances without affecting histamine release. 3. These results with human lung tissue in vitro suggest that benoxaprofen may be used to investigate the role of slow-reacting substances in experimental and clinical asthma.

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