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Respiratory Research Jun 2009Diseases featuring abnormally low alveolar PO2 are frequently accompanied by systemic effects. The common presence of an underlying inflammatory component suggests that... (Review)
Review
Diseases featuring abnormally low alveolar PO2 are frequently accompanied by systemic effects. The common presence of an underlying inflammatory component suggests that inflammation may contribute to the pathogenesis of the systemic effects of alveolar hypoxia. While the role of alveolar macrophages in the immune and defense functions of the lung has been long known, recent evidence indicates that activation of alveolar macrophages causes inflammatory disturbances in the systemic microcirculation. The purpose of this review is to describe observations in experimental animals showing that alveolar macrophages initiate a systemic inflammatory response to alveolar hypoxia. Evidence obtained in intact animals and in primary cell cultures indicate that alveolar macrophages activated by hypoxia release a mediator(s) into the circulation. This mediator activates perivascular mast cells and initiates a widespread systemic inflammation. The inflammatory cascade includes activation of the local renin-angiotensin system and results in increased leukocyte-endothelial interactions in post-capillary venules, increased microvascular levels of reactive O2 species; and extravasation of albumin. Given the known extrapulmonary responses elicited by activation of alveolar macrophages, this novel phenomenon could contribute to some of the systemic effects of conditions featuring low alveolar PO2.
Topics: Animals; Humans; Hypoxia; Inflammation; Ischemia; Lung Diseases; Macrophage Activation; Macrophages, Alveolar; Rats
PubMed: 19545431
DOI: 10.1186/1465-9921-10-54 -
PLoS Pathogens Jul 2023Although alveolar macrophages (AMs) play important roles in preventing and eliminating pulmonary infections, little is known about their regulation in healthy animals....
Although alveolar macrophages (AMs) play important roles in preventing and eliminating pulmonary infections, little is known about their regulation in healthy animals. Since exposure to LPS often renders cells hyporesponsive to subsequent LPS exposures ("tolerant"), we tested the hypothesis that LPS produced in the intestine reaches the lungs and stimulates AMs, rendering them tolerant. We found that resting AMs were more likely to be tolerant in mice lacking acyloxyacyl hydrolase (AOAH), the host lipase that degrades and inactivates LPS; isolated Aoah-/- AMs were less responsive to LPS stimulation and less phagocytic than were Aoah+/+ AMs. Upon innate stimulation in the airways, Aoah-/- mice had reduced epithelium- and macrophage-derived chemokine/cytokine production. Aoah-/- mice also developed greater and more prolonged loss of body weight and higher bacterial burdens after pulmonary challenge with Pseudomonas aeruginosa than did wildtype mice. We also found that bloodborne or intrarectally-administered LPS desensitized ("tolerized") AMs while antimicrobial drug treatment that reduced intestinal commensal Gram-negative bacterial abundance largely restored the innate responsiveness of Aoah-/- AMs. Confirming the role of LPS stimulation, the absence of TLR4 prevented Aoah-/- AM tolerance. We conclude that commensal LPSs may stimulate and desensitize (tolerize) alveolar macrophages in a TLR4-dependent manner and compromise pulmonary immunity. By inactivating LPS in the intestine, AOAH promotes antibacterial host defenses in the lung.
Topics: Animals; Mice; Lipopolysaccharides; Lung; Macrophages, Alveolar; Toll-Like Receptor 4; Carboxylic Ester Hydrolases
PubMed: 37498977
DOI: 10.1371/journal.ppat.1011556 -
Frontiers in Immunology 2023
Topics: Lung; Macrophages, Alveolar
PubMed: 38045688
DOI: 10.3389/fimmu.2023.1332852 -
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 -
Frontiers in Immunology 2018Hyaluronan is a hygroscopic glycosaminoglycan that contributes to both extracellular and pericellular matrices. While the production of hyaluronan is essential for... (Review)
Review
Hyaluronan is a hygroscopic glycosaminoglycan that contributes to both extracellular and pericellular matrices. While the production of hyaluronan is essential for mammalian development, less is known about its interaction and function with immune cells. Here we review what is known about hyaluronan in the lung and how it impacts immune cells, both at homeostasis and during lung inflammation and fibrosis. In the healthy lung, alveolar macrophages provide the first line of defense and play important roles in immunosurveillance and lipid surfactant homeostasis. Alveolar macrophages are surrounded by a coat of hyaluronan that is bound by CD44, a major hyaluronan receptor on immune cells, and this interaction contributes to their survival and the maintenance of normal alveolar macrophage numbers. Alveolar macrophages are conditioned by the alveolar environment to be immunosuppressive, and can phagocytose particulates without alerting an immune response. However, during acute lung infection or injury, an inflammatory immune response is triggered. Hyaluronan levels in the lung are rapidly increased and peak with maximum leukocyte infiltration, suggesting a role for hyaluronan in facilitating leukocyte access to the injury site. Hyaluronan can also be bound by hyaladherins (hyaluronan binding proteins), which create a provisional matrix to facilitate tissue repair. During the subsequent remodeling process hyaluronan concentrations decline and levels return to baseline as homeostasis is restored. In chronic lung diseases, the inflammatory and/or repair phases persist, leading to sustained high levels of hyaluronan, accumulation of associated immune cells and an inability to resolve the inflammatory response.
Topics: Animals; Humans; Hyaluronic Acid; Inflammation; Lung; Macrophages, Alveolar; Pneumonia
PubMed: 30555472
DOI: 10.3389/fimmu.2018.02787 -
International Journal of Molecular... Mar 2021Macrophages act as immune scavengers and are important cell types in the homeostasis of various tissues. Given the multiple roles of macrophages, these cells can also be... (Review)
Review
Macrophages act as immune scavengers and are important cell types in the homeostasis of various tissues. Given the multiple roles of macrophages, these cells can also be found as tissue resident macrophages tightly integrated into a variety of tissues in which they fulfill crucial and organ-specific functions. The lung harbors at least two macrophage populations: interstitial and alveolar macrophages, which occupy different niches and functions. In this review, we provide the latest insights into the multiple roles of alveolar macrophages while unraveling the distinct factors which can influence the ontogeny and function of these cells. Furthermore, we will highlight pulmonary diseases, which are associated with dysfunctional macrophages, concentrating on congenital diseases as well as pulmonary infections and impairment of immunological pathways. Moreover, we will provide an overview about different treatment approaches targeting macrophage dysfunction. Improved knowledge of the role of macrophages in the onset of pulmonary diseases may provide the basis for new pharmacological and/or cell-based immunotherapies and will extend our understanding to other macrophage-related disorders.
Topics: Animals; Homeostasis; Humans; Macrophages, Alveolar; Pulmonary Alveolar Proteinosis; Pulmonary Surfactants
PubMed: 33804918
DOI: 10.3390/ijms22073308 -
The American Journal of the Medical... Mar 2012Alcohol use, and misuse, has been a part of human culture for thousands of years. In the modern medical era, a great deal of attention has been justifiably focused on... (Review)
Review
Alcohol use, and misuse, has been a part of human culture for thousands of years. In the modern medical era, a great deal of attention has been justifiably focused on elucidating the mechanisms underlying the psychological and biological addiction to alcohol. However, a significant percentage, if not the majority, of alcohol-related morbidity and mortality occurs in individuals who do not meet the formal diagnostic criteria for alcohol use disorders. For example, many serious medical consequences of chronic alcohol ingestion can occur in individuals who do not have signs or symptoms of alcohol dependence. There is now clear evidence that even in otherwise healthy-appearing individuals who chronically consume excessive amounts of alcohol, alveolar macrophage immune capacity is impaired and, as a consequence, these individuals are at significantly increased risk of pneumonia. This brief review summarizes some of the key mechanisms underlying this phenomenon and proposes a hypothetical scheme by which alcohol interferes with zinc bioavailability within the alveolar space and thereby dampens macrophage function.
Topics: Alcoholism; Animals; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Macrophages, Alveolar; Mice; Pneumonia; Signal Transduction; Zinc
PubMed: 22173040
DOI: 10.1097/MAJ.0b013e31823ede77 -
JCI Insight Apr 2022Tissue-resident macrophage-based immune therapies have been proposed for various diseases. However, generation of sufficient numbers that possess tissue-specific...
Tissue-resident macrophage-based immune therapies have been proposed for various diseases. However, generation of sufficient numbers that possess tissue-specific functions remains a major handicap. Here, we showed that fetal liver monocytes cultured with GM-CSF (CSF2-cFLiMo) rapidly differentiated into a long-lived, homogeneous alveolar macrophage-like population in vitro. CSF2-cFLiMo retained the capacity to develop into bona fide alveolar macrophages upon transfer into Csf2ra-/- neonates and prevented development of alveolar proteinosis and accumulation of apoptotic cells for at least 1 year in vivo. CSF2-cFLiMo more efficiently engrafted empty alveolar macrophage niches in the lung and protected mice from severe pathology induced by respiratory viral infection compared with transplantation of macrophages derived from BM cells cultured with M-CSF (CSF1-cBMM) in the presence or absence of GM-CSF. Harnessing the potential of this approach for gene therapy, we restored a disrupted Csf2ra gene in fetal liver monocytes and demonstrated their capacity to develop into alveolar macrophages in vivo. Altogether, we provide a platform for generation of immature alveolar macrophage-like precursors amenable for genetic manipulation, which will be useful to dissect alveolar macrophage development and function and for pulmonary transplantation therapy.
Topics: Animals; Genetic Diseases, X-Linked; Genetic Therapy; Granulocyte-Macrophage Colony-Stimulating Factor; Macrophages, Alveolar; Mice; Monocytes; Pulmonary Alveolar Proteinosis
PubMed: 35393945
DOI: 10.1172/jci.insight.152271 -
The European Respiratory Journal Jun 2021Respiratory syncytial virus (RSV) is the major cause of acute bronchiolitis in infants under 2 years old. Necroptosis has been implicated in the outcomes of...
Respiratory syncytial virus (RSV) is the major cause of acute bronchiolitis in infants under 2 years old. Necroptosis has been implicated in the outcomes of respiratory virus infections. We report that RSV infection triggers necroptosis in primary mouse macrophages and human monocytes in a RIPK1-, RIPK3- and MLKL-dependent manner. Moreover, necroptosis pathways are harmful to RSV clearance from alveolar macrophages. Additionally, mice were protected from RSV-induced weight loss and presented with reduced viral loads in the lungs.Alveolar macrophage depletion also protected mice from weight loss and decreased lung RSV virus load. Importantly, alveolar macrophage depletion abolished the upregulation of and gene expression induced by RSV infection in the lung tissue.Autocrine tumor necrosis factor (TNF)-mediated RSV-triggered macrophage necroptosis and necroptosis pathways were also involved in TNF secretion even when macrophages were committed to cell death, which can worsen lung injury during RSV infection. In line, mice had a marked decrease in and gene expression and a sharp reduction in the numbers of necrotic alveolar macrophages in the lungs. Finally, we provide evidence that elevated nasal levels of TNF are associated with disease severity in infants with RSV bronchiolitis.We propose that targeting TNF and/or the necroptotic machinery may be valuable therapeutic approaches to reduce the respiratory morbidity caused by RSV infection in young children.
Topics: Animals; Bronchiolitis; Macrophages, Alveolar; Mice; Necroptosis; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human
PubMed: 33303545
DOI: 10.1183/13993003.03764-2020 -
Frontiers in Immunology 2021The human innate host defense molecules, SP-A1 and SP-A2 variants, differentially affect survival after infection in mice and in lung transplant patients. SP-A interacts... (Review)
Review
Human Surfactant Protein SP-A1 and SP-A2 Variants Differentially Affect the Alveolar Microenvironment, Surfactant Structure, Regulation and Function of the Alveolar Macrophage, and Animal and Human Survival Under Various Conditions.
The human innate host defense molecules, SP-A1 and SP-A2 variants, differentially affect survival after infection in mice and in lung transplant patients. SP-A interacts with the sentinel innate immune cell in the alveolus, the alveolar macrophage (AM), and modulates its function and regulation. SP-A also plays a role in pulmonary surfactant-related aspects, including surfactant structure and reorganization. For most (if not all) pulmonary diseases there is a dysregulation of host defense and inflammatory processes and/or surfactant dysfunction or deficiency. Because SP-A plays a role in both of these general processes where one or both may become aberrant in pulmonary disease, SP-A stands to be an important molecule in health and disease. In humans (unlike in rodents) SP-A is encoded by two genes ( and ) and each has been identified with extensive genetic and epigenetic complexity. In this review, we focus on functional, structural, and regulatory differences between the two SP-A gene-specific products, SP-A1 and SP-A2, and among their corresponding variants. We discuss the differential impact of these variants on the surfactant structure, the alveolar microenvironment, the regulation of epithelial type II miRNome, the regulation and function of the AM, the overall survival of the organism after infection, and others. Although there have been a number of reviews on SP-A, this is the first review that provides such a comprehensive account of the differences between human SP-A1 and SP-A2.
Topics: Amino Acid Sequence; Amino Acid Substitution; Animals; Biomarkers; Cellular Microenvironment; Disease Susceptibility; Genetic Variation; Humans; Macrophages, Alveolar; Mice; Models, Biological; Proteome; Proteomics; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactants; Structure-Activity Relationship
PubMed: 34484180
DOI: 10.3389/fimmu.2021.681639