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Toxicology Letters Oct 2020Despite many studies investigating the mechanism of Sulfur Mustard (SM) induced lung injury, the underlying mechanism is still unclear. Inflammatory and subsequent... (Review)
Review
Despite many studies investigating the mechanism of Sulfur Mustard (SM) induced lung injury, the underlying mechanism is still unclear. Inflammatory and subsequent fibroproliferative stages of SM-toxicity are based upon several highly-related series of events controlled by the immune system. The inhalation of SM gas variably affects different cell populations within the lungs. Various studies have shown the critical role of macrophages in triggering a pulmonary inflammatory response as well as its maintenance, resolution, and repair. Importantly, macrophages can serve as either pro-inflammatory or anti-inflammatory populations depending on the present conditions at any pathological stage. Different characteristics of macrophages, including their differentiation, phenotypic, and functional properties, as well as interactions with other cell populations determine the outcomes of lung diseases and the extent of long- or short-term pulmonary damage induced by SM. In this paper, we summarize the current state of knowledge regarding the role of alveolar macrophages and their mediators in the pathogenesis of SM in pulmonary injury. Investigating the specific cells and mechanisms involved in SM-lung injury may be useful in finding new target opportunities for treatment of this injury.
Topics: Adaptive Immunity; Animals; Chemical Warfare Agents; Humans; Immunity, Innate; Immunity, Mucosal; Lung; Macrophages, Alveolar; Mustard Gas
PubMed: 32758513
DOI: 10.1016/j.toxlet.2020.07.035 -
International Immunopharmacology Jun 2022Alveolar macrophages (AMs) play a demonstrative role in acute lung injury (ALI). Exosomes act as signaling molecules to regulate cell-to-cell communication by releasing...
BACKGROUND
Alveolar macrophages (AMs) play a demonstrative role in acute lung injury (ALI). Exosomes act as signaling molecules to regulate cell-to-cell communication by releasing RNAs. Transfer RNA-derived fragments (tRFs) possess potential functions in multiple diseases through ferroptosis. The present study aims to reveal the role of AM-derived exosomal tRFs in ALI and to identify the relationship to ferroptosis.
METHODS
ALI mice model was established by lipopolysaccharide (LPS) induction. RNA sequencing was performed to identify the tRFs profile in bronchoalveolar lavage fluid (BALF) exosomes of ALI mice. After interfering with the expression of candidate tRFs in AMs or alveolar epithelial cells (MLE-12), the effect of oxidative stress and expression of ferroptosis-related proteins were detected.
RESULTS
Exosomes isolated from BALF of ALI mice were dominated by a macrophage immunophenotype. RNA-sequencing identified 4 up- and 10 down-regulated differentially expressed tRFs (DEtRFs), among which tRF-22-8BWS7K092 expression was significantly increased in LPS-induced macrophage-derived exosomes (LPS-exo). Hippo signaling pathway was the most significantly enriched KEGG pathways for DEtRFs. LPS-exo inhibited cell viability and the expression of GPX4 and FTH1, and enhanced oxidative stress in MLE-12 cells. Ferroptosis inhibitor reversed the inhibition of LPS-exo on cell viability and tRF-22-8BWS7K092 inhibitor rescued above effect of LPS-exo on MLE-12 cells. Besides, tRF-22-8BWS7K092 could activate Hippo signaling pathway by binding Wnt5B, inducing ferroptosis in MLE-12 cells.
CONCLUSION
BALF exosomes of ALI mice were mainly derived from AMs. AM-derived exosomal tRF-22-8BWS7K092 activates the Hippo signaling pathway to induce ferroptosis, thus contributing to the pathogenesis of ALI.
Topics: Acute Lung Injury; Animals; Ferroptosis; Hippo Signaling Pathway; Lipopolysaccharides; Macrophages, Alveolar; Mice; Mice, Inbred C57BL
PubMed: 35299002
DOI: 10.1016/j.intimp.2022.108690 -
The Journal of Laboratory and Clinical... Jun 1999
Review
Topics: Animals; Cytokines; Humans; Macrophages, Alveolar; Oxidants; Pneumocystis; Pneumonia, Pneumocystis; Pulmonary Surfactants
PubMed: 10360627
DOI: 10.1016/s0022-2143(99)90182-8 -
Thorax Nov 2016Microvesicles (MVs) are important mediators of intercellular communication, packaging a variety of molecular cargo. They have been implicated in the pathophysiology of...
BACKGROUND
Microvesicles (MVs) are important mediators of intercellular communication, packaging a variety of molecular cargo. They have been implicated in the pathophysiology of various inflammatory diseases; yet, their role in acute lung injury (ALI) remains unknown.
OBJECTIVES
We aimed to identify the biological activity and functional role of intra-alveolar MVs in ALI.
METHODS
Lipopolysaccharide (LPS) was instilled intratracheally into C57BL/6 mice, and MV populations in bronchoalveolar lavage fluid (BALF) were evaluated. BALF MVs were isolated 1 hour post LPS, assessed for cytokine content and incubated with murine lung epithelial (MLE-12) cells. In separate experiments, primary alveolar macrophage-derived MVs were incubated with MLE-12 cells or instilled intratracheally into mice.
RESULTS
Alveolar macrophages and epithelial cells rapidly released MVs into the alveoli following LPS. At 1 hour, the dominant population was alveolar macrophage-derived, and these MVs carried substantive amounts of tumour necrosis factor (TNF) but minimal amounts of IL-1β/IL-6. Incubation of these mixed MVs with MLE-12 cells induced epithelial intercellular adhesion molecule-1 (ICAM-1) expression and keratinocyte-derived cytokine release compared with MVs from untreated mice (p<0.001). MVs released in vitro from LPS-primed alveolar macrophages caused similar increases in MLE-12 ICAM-1 expression, which was mediated by TNF. When instilled intratracheally into mice, these MVs induced increases in BALF neutrophils, protein and epithelial cell ICAM-1 expression (p<0.05).
CONCLUSIONS
We demonstrate, for the first time, the sequential production of MVs from different intra-alveolar precursor cells during the early phase of ALI. Our findings suggest that alveolar macrophage-derived MVs, which carry biologically active TNF, may play an important role in initiating ALI.
Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Cell-Derived Microparticles; Cytokines; Lipopolysaccharides; Macrophages, Alveolar; Mice; Mice, Inbred C57BL
PubMed: 27287089
DOI: 10.1136/thoraxjnl-2015-208032 -
Biomaterials May 2019Nanocellulose is a promising bio-nanomaterial with attractive properties suitable for multiple industrial applications. The increased use of nanocellulose may lead to...
Nanocellulose is a promising bio-nanomaterial with attractive properties suitable for multiple industrial applications. The increased use of nanocellulose may lead to occupational exposure and negative health outcomes. However, knowledge on its health effects is limited, and while nanocellulose exposure may induce acute inflammatory responses in the lung, the underlying mechanisms are unknown. Alveolar macrophages are key cells in alveolar particle clearance. Their activation and function may be affected by various particles. Here, we investigated the uptake of pristine cellulose nanocrystals (CNC), and their effects on alveolar macrophage polarization and biological function. CNC uptake enhanced the secretion of several cytokines but did not on its own induce a complete macrophage polarization. In presence of macrophage activators, such as LPS/IFNG and IL4/IL13, CNC exposure enhanced the expression of M1 phenotype markers and the secretion of pro-inflammatory cytokines and chemokines, while decreasing M2 markers. CNC exposure also affected the function of activated alveolar macrophages resulting in a prominent cytokine burst and altered phagocytic activity. In conclusion, CNC exposure may result in dysregulation of macrophage activation and function that are critical in inflammatory responses in the lung.
Topics: Animals; Cell Line; Cell Proliferation; Cell Survival; Cellulose; Macrophages, Alveolar; Mice; Microscopy, Electron, Scanning; Nanoparticles; Phagocytes; Phagocytosis; Phenotype
PubMed: 30851491
DOI: 10.1016/j.biomaterials.2019.02.025 -
Toxicology and Applied Pharmacology Sep 2023One of the main hurdles in the development of new inhaled medicines is the frequent observation of foamy macrophage (FM) responses in non-clinical studies in...
One of the main hurdles in the development of new inhaled medicines is the frequent observation of foamy macrophage (FM) responses in non-clinical studies in experimental animals, which raises safety concerns and hinders progress into clinical trials. We have investigated the potential of a novel multi-parameter high content image analysis (HCIA) assay as an in vitro safety screening tool to predict drug induced FM. Rat (NR8383) and human U937-derived alveolar macrophages were exposed in vitro to a panel of model compounds with different biological activity, including inhaled bronchodilators, inhaled corticosteroids (ICS), phospholipidosis inducers and proapoptotic agents. An HCIA was utilized to produce drug-induced cell response profiles based on individual cell health, morphology and lipid content parameters. The profiles of both rat and human macrophage cell lines differentiated between cell responses to marketed inhaled drugs and compounds known to induce phospholipidosis and apoptosis. Hierarchical clustering of the aggregated data allowed identification of distinct cell profiles in response to exposure to phospholipidosis and apoptosis inducers. Additionally, in NR8383 cell responses formed two distinct clusters, associated with increased vacuolation with or without lipid accumulation. U937 cells presented a similar trend but appeared less sensitive to drug exposure and presented a narrower range of responses. These results indicate that our multi-parameter HCIA assay is suitable to generate characteristic drug-induced macrophage response profiles, thus enabling differentiation of foamy macrophage phenotypes associated with phospholipidosis and apoptosis. This approach shows great potential as pre-clinical in vitro screening tool for safety assessment of candidate inhaled medicines.
Topics: Rats; Humans; Animals; Macrophages, Alveolar; Macrophages; Foam Cells; Cell Line; Lipids
PubMed: 37385476
DOI: 10.1016/j.taap.2023.116608 -
Retrovirology Sep 2020As HIV has fueled a global resurgence of tuberculosis over the last several decades, there is a growing awareness that HIV-mediated impairments in both innate and... (Review)
Review
As HIV has fueled a global resurgence of tuberculosis over the last several decades, there is a growing awareness that HIV-mediated impairments in both innate and adaptive immunity contribute to the heightened risk of tuberculosis in people with HIV. Since early immune responses to Mycobacterium tuberculosis (Mtb) set the stage for subsequent control or progression to active tuberculosis disease, early host-pathogen interactions following Mtb infection can be thought of as establishing a mycobacterial "set point," which we define as the mycobacterial burden at the point of adaptive immune activation. This early immune response is impaired in the context of HIV coinfection, allowing for a higher mycobacterial set point and greater likelihood of progression to active disease with greater bacterial burden. Alveolar macrophages, as the first cells to encounter Mtb in the lungs, play a critical role in containing Mtb growth and establishing the mycobacterial set point. However, a number of key macrophage functions, ranging from pathogen recognition and uptake to phagocytosis and microbial killing, are blunted in HIV coinfection. To date, research evaluating the effects of HIV on the alveolar macrophage response to Mtb has been relatively limited, particularly with regard to the critical early events that help to dictate the mycobacterial set point. A greater understanding of alveolar macrophage functions impacted by HIV coinfection will improve our understanding of protective immunity to Mtb and may reveal novel pathways amenable to intervention to improve both early immune control of Mtb and clinical outcomes for the millions of people worldwide infected with HIV.
Topics: AIDS-Related Opportunistic Infections; Adaptive Immunity; Bacterial Load; Cell Death; Cytokines; HIV; Humans; Immunity, Innate; Macrophages, Alveolar; Models, Biological; Mycobacterium tuberculosis; Oxidative Stress; Phagocytosis; Tuberculosis
PubMed: 32967690
DOI: 10.1186/s12977-020-00540-2 -
Signal Transduction and Targeted Therapy Dec 2021
Topics: COVID-19; Endosomes; Humans; Macrophages, Alveolar; SARS-CoV-2
PubMed: 34921130
DOI: 10.1038/s41392-021-00845-4 -
Methods (San Diego, Calif.) Jul 2000Inhaled particulates such as pollutant particles, allergens, and microorganisms are rapidly cleared by alveolar macrophages (AMs). Methods for analysis of AM-particle... (Review)
Review
Inhaled particulates such as pollutant particles, allergens, and microorganisms are rapidly cleared by alveolar macrophages (AMs). Methods for analysis of AM-particle interaction have been hindered by the lack of a convenient assay. Flow cytometry offers rapid, sensitive, and reproducible measurements of single cells in suspension. Multiple parameters can be measured in real time. Here we will review the application of flow cytometry to the study and characterization of AM receptors for unopsonized environmental particles. We will discuss the role of this technique in identifying a key AM receptor system involved in lung defense. Multiparametric flow cytometry to analyze intracellular functional parameters, though a powerful and unique tool, needs to be interpreted with caution. We will also discuss the advantages and limitations of flow cytometry in analysis of AM-particle interaction.
Topics: Allergens; Animals; Environmental Pollutants; Flow Cytometry; Lung; Macrophages, Alveolar; Phagocytosis; Pulmonary Surfactants; Receptors, Cell Surface; Respiratory Burst
PubMed: 10873478
DOI: 10.1006/meth.2000.1004 -
Toxicology and Applied Pharmacology Feb 2023Macrophage efferocytosis of apoptotic neutrophils (PMNs) plays a key role in the resolution of inflammation. In these studies, we describe a novel flow cytometric method...
Macrophage efferocytosis of apoptotic neutrophils (PMNs) plays a key role in the resolution of inflammation. In these studies, we describe a novel flow cytometric method to assess efferocytosis of apoptotic PMNs. Resident alveolar macrophages and PMNs were collected from lungs of mice exposed to inhaled ozone (0.8 ppm, 3 h) followed by lipopolysaccharide (3 mg/kg, i.v.) to induce acute lung injury. PMNs were labeled with PKH26 or DilC(5)-DS (D12730) cell membrane dye and then incubated with resident alveolar macrophages at a ratio of 5:1. After 90 min, macrophage efferocytosis was analyzed by flow cytometry and confirmed by confocal microscopy. Whereas alveolar macrophages incubated with D12730-labeled PMNs could readily be identified as efferocytotic or non-efferocytotic, this was not possible with PKH26 labeled PMNs due to confounding macrophage autofluorescence. Using D12730 labeled PMNs, subsets of resident alveolar macrophages were identified with varying capacities to perform efferocytosis, which may be linked to the activation state of these cells. Future applications of this method will be useful in assessing the role of efferocytosis in the resolution of inflammation in response to toxicant exposure.
Topics: Mice; Animals; Neutrophils; Macrophages, Alveolar; Flow Cytometry; Phagocytosis; Inflammation; Apoptosis
PubMed: 36565939
DOI: 10.1016/j.taap.2022.116359