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An alveolar macrophage (or dust cell) is a type of macrophage found in the pulmonary alveolus, near the pneumocytes, but separated from the wall. Activity of the alveolar macrophage is relatively high, because they are located at one of the major boundaries between the body and the outside world. Dust cells are another name for monocyte derivatives in the lungs that reside on respiratory surfaces and clean off particles such as dust or microorganisms. Alveolar macrophages are frequently seen to contain granules of exogenous material such as particulate carbon that they have picked up from respiratory surfaces. Such black granules may be especially common in smoker's lungs or long-term city dwellers. Inhaled air may contain particles or organisms which would be pathogenic. The respiratory pathway is a prime site for exposure to pathogens and toxic substances. The respiratory tree, comprising the larynx, trachea, and bronchioles, is lined by ciliated epithelia cells that are continually exposed to harmful matter.〔Hussain, Aliya N. “Immune system of the lungs”. Pathologic basis of disease7 (2006): Chapter 15〕 When these offensive agents infiltrate the superficial barriers, the body's immune system responds in an orchestrated defense involving a litany of specialized cells which target the threat, neutralize it, and clean up the remnants of the battle. Deep within the lungs exists its constituent alveoli sacs, the sites responsible for the uptake of oxygen and excretion of carbon dioxide. There are three major alveolar cell types in the alveolar wall (pneumocytes): * Type I pneumocyte (Squamous Alveolar) cells that form the structure of an alveolar wall. * Type II pneumocyte (Great Alveolar) cells that secrete pulmonary surfactant to lower the surface tension of water and allows the membrane to separate, thereby increasing the capability to exchange gases. Surfactant is continuously released by exocytosis. It forms an underlying aqueous protein-containing hypophase and an overlying phospholipid film composed primarily of dipalmitoyl phosphatidylcholine. * Macrophages that destroy foreign material, such as bacteria. Type 1 and type 2 pneumocytes.〔Lambrecht, B. N. "Alveolar Macrophage in the Driver's Seat." Immunity 24.4 (2006): 366-8.〕 Type 1 pneumocytes (or membranous pneumocytes) form the structure of the alveolus and are responsible for the gas exchange in the alveolus.〔Guyton, Arthur C. “Physiology of the respiratory system.” ''Textbook of Medical Physiology'' 11(2007): Chapter 33, 431-433〕 Type 1 pneumocytes are squamous epithelial cells which are characterized by a superficial layer consisting of large, thin, scale-like cells; they also cover 95% of the alveolar surface, although they are only half as numerous as Type 2 pneumocytes.〔〔 Type 2 pneumocytes are important in that they can proliferate and differentiate into type 1 pneumocytes, which cannot replicate and are susceptible to a vast numbers of toxic insults.〔 Type 2 pneumocytes are also important because they secrete pulmonary surfactant(PS), which consists 80-90% of phospholipids (phosphatidyglycerol(PG), phosphaditylinositol (PI) ) and 5-10% of surfactant proteins (SP-A, SP-B, SP-C, AND SP-D).〔oshizawa, S., et al. "Legionella Pneumophila Evades Gamma Interferon-Mediated Growth Suppression through Interleukin-10 Induction in Bone Marrow-Derived Macrophages." ''Infection and immunity'' 73.5 (2005): 2709-17.〕 PS is synthesized as lamellar bodies, which are structures consisting of closely packed bilayers that are secreted and then undergo transformation into a morphological form called tubular myelin.〔 PS plays an important role in maintaining normal respiratory mechanics by reducing alveolar surface tension. By lowering alveolar surface tension, PS reduces the energy required to inflate the lungs, and reduces the likelihood of alveolar collapse during expiration.〔 Loosely attached to these alveoli sacs are the alveolar macrophages that protect the lungs from a broad array of microbes and aerosols by devouring and ingesting them through phagocytosis.〔 Alveolar macrophages are phagocytes that play a critical role in homeostasis, host defense, the response to foreign substances, and tissue remodeling.〔 Since alveolar macrophages are pivotal regulators of local immunological homeostasis, their population density is decisive for the many processes of immunity in the lungs. They are highly adaptive components of the innate immune system and can be specifically modified to whatever functions needed depending on their state of differentiation and micro-environmental factors encountered. Alveolar macrophages release numerous secretory products and interact with other cells and molecules through the expression of several surface receptors. Alveolar macrophages are also involved in the phagocytosis of apoptotic and necrotic cells that have undergone cell-death.〔 They must be selective of the material that is phagocytized because normal cells and structures of the body must not be compromised.〔 To combat infection, the phagocytes of the innate immune system facilitates many pattern recognition receptors (PRR) to help recognize pathogen-associated molecular patterns (PAMPs) on the surface of pathogenic microorganisms.〔Stafford, J. L., N. F. Neumann, and M. Belosevic. "Macrophage-Mediated Innate Host Defense Against Protozoan Parasites." ''Critical reviews in microbiology'' 28.3 (2002): 187-248.〕 PAMPs all have the common features of being unique to a group of pathogens but invariant in their basic structure; and are essential for pathogenicity(ability of an organism to produce an infectious disease in another organism).〔 Proteins involved in microbial pattern recognition include mannose receptor, complement receptors, DC-SIGN,Toll-like receptors(TLRs), the scavenger receptor, CD14, and Mac-1.〔〔Krutzik, Stephan R., and Robert L. Modlin. "The Role of Toll-Like Receptors in Combating Mycobacteria." ''Seminars in Immunology'', 16.1 (2004): 35-41.〕 PRRs can be divided into three classes: #signaling PRRs that activate gene transcriptional mechanisms that lead to cellular activation, #endocytic PRRs that function in pathogen binding and phagocytosis, and #secreted PRRs that usually function as opsonins or activators of complement. The recognition and clearance of invading microorganisms occurs through both opsonin-dependent and opsonin–independent pathways. The molecular mechanisms facilitating opsonin-dependent phagocytosis are different for specific opsonin/receptor pairs. For example, phagocytosis of IgG-opsonized pathogens occurs through the Fcγ receptors (FcγR), and involves phagocyte extensions around the microbe, resulting in the production of pro-inflammatory mediators. Conversely, complement receptor-mediated pathogen ingestion occurs without observable membrane extensions (particles just sink into the cell) and does not generally results in an inflammatory mediator response. Following internalization, the microbe is enclosed in a vesicular phagosome which then undergoes fusion with primary or secondary lysosomes, forming a phagolysosome.〔 There are various mechanisms that lead to intracellular killing; there are oxidative processes, and others independent of the oxidative metabolism. The former involves the activation of membrane enzyme systems that lead to a stimulation of oxygen uptake (known as the respiratory burst), and its reduction to reactive oxygen intermediates (ROIs), molecular species that are highly toxic for microorganisms.〔 The enzyme responsible for the elicitation of the respiratory burst is known as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which is composed of five subunits.〔 One component is a membrane cytochrome made up of two protein subunits, gp91phox and p22phox; the remaining three components are cytosolic-derived proteins: p40phox, p47phox, and p67phox.〔 NADPH oxidase exists in the cytosol of the AM when in a quiescent state; but upon activation, two of its cytosolic components, p47phox and p67phox, have their tyrosine and serine residues phosphorylated, which are then able to mediate translocation of NADPHox to the cytochrome component, gp91phox/p22phox, on the plasma membrane via cytoskeletal elements.〔〔Serezani, C. H., et al. "Prostaglandin E2 Suppresses Bacterial Killing in Alveolar Macrophages by Inhibiting NADPH Oxidase." ''American journal of respiratory cell and molecular biology'' 37.5 (2007): 562-70.〕 Compared to other phagocytes, the respiratory burst in AM is of a greater magnitude.〔 Oxygen-independent microbicidal mechanisms are based on the production of acid, on the secretion of lysozymes, on iron-binding proteins, and on the synthesis of toxic cationic polypeptides.〔 Macrophages possess a repertoire of antimicrobial molecules packaged within their granules and lysosomes.〔 These organelles contain a plethora of degradative enzymes and antimicrobial peptides that are released into the phagolysosome, such as proteases, nucleases, phosphatases, esterases, lipases, and highly basic peptides.〔 Moreover, macrophages possess a number of nutrient deprivation mechanisms that are used to starve phagocytosed pathogens of essential micronutrients.〔 Certain microorganisms have evolved countermeasures which enable them to evade being destroyed by phagocytes. Although lysosomal-mediated degradation is an efficient means by which to neutralize an infection and prevent colonization, several pathogens parasitize macrophages, exploiting them as a host cell for growth, maintenance and replication.〔 Parasites like Toxoplasma gondii and mycobacteria are able to prevent fusion of phagosomes with lysosomes, thus escaping the harmful action of lysosomal hydrolases. Others avoid lysosomes by leaving the phagocytic vacuole, to reach the cytosolic matrix where their development is unhindered. In these instances, macrophages may be triggered to actively destroy phagocytosed microorganisms by producing a number of highly toxic molecules and inducing deprivational mechanism to starve it.〔 Finally, some microbes have enzymes to detoxify oxygen metabolites formed during the respiratory burst.〔 When insufficient to ward off the threat, alveolar macrophages can release proinflammatory cytokines and chemokines to call forth a highly developed network of defensive phagocytic cells responsible for the adaptive immune response. The lungs are especially sensitive and prone to damage, thus to avoid collateral damage to type 1 and type II pneumocytes, alveolar macrophages are kept in a quiescent state, producing little inflammatory cytokines and displaying little phagocytic activity, as evidenced by downregulated expression of the phagocytic receptor Macrophage 1 antigen (Mac-1).〔〔Holt, P. G., et al. "Downregulation of the Antigen Presenting Cell Function(s) of Pulmonary Dendritic Cells in Vivo by Resident Alveolar Macrophages." The Journal of experimental medicine 177.2 (1993): 397-407.〕 AMs actively suppress the induction of two of the immunity systems of the body: the adaptive immunity and humoral immunity. The adaptive immunity is suppressed through AM’s effects on interstitial dendritic cells, B-cells and T-cells, as these cells are less selective of what they destroy, and often cause unnecessary damage to normal cells. To prevent uncontrolled inflammation in the lower respiratory tract, alveolar macrophages secrete nitric oxide, prostaglandins, interleukin-4 and -10(IL-4, IL-10), and transforming growth factor-β (TGF-β).〔〔BUNN, H. J., C. R. A. HEWITT, and J. GRIGG. "Suppression of Autologous Peripheral Blood Mononuclear Cell Proliferation by Alveolar Macrophages from Young Infants." Clinical & Experimental Immunology 128.2 (2002): 313-7.〕〔Bingisser, R. M., and P. G. Holt. " Swiss medical weekly : official journal of the Swiss Society of Infectious Diseases, the Swiss Society of Internal Medicine, the Swiss Society of Pneumology 131.13-14 (2001): 171-9.〕〔Lacraz, S., et al. "Suppression of Metalloproteinase Biosynthesis in Human Alveolar Macrophages by Interleukin-4." ''The Journal of clinical investigation'' 90.2 (1992): 382-8.〕 ==Nitric Oxide== NO is a major source of immunomodulation in rodents, and is produced by enzyme nitric oxide synthetase type 2 (NOS2) in the alveolar macrophage.〔 NO inhibits tyrosine phosphorylation of the kinases involved in production of the interleukin-2 (IL-2) receptor, the expression of which is fundamental for T cell proliferation.〔 In humans, however, NOS2 activity has been difficult to verify.〔 There are two explanations for the lack of responsiveness in the promoter of human inducible nitric oxide synthetase (iNOS) to NO activation by lipopolysaccharides (LPS) + interferon-gamma (IFN-γ).〔 The first is that there are various inactivating nucleotide variations in the human counterpart of the enhancer element that regulates LPS/IFN-γ induced expression of the mouse NOS2 gene. The second is because of the absence of a nuclear factor in human macrophages that is required for optimum expression of gene NOS2 (LPS-inducible nuclear factor-kappa B/Rel complex).〔 It is assumed that the difficulty in verifying NOS2 is due to a much more tightly controlled expression in human AMs as compared to that in the rodent AMs.〔 NOS2 is part of an autoregulatory feedback loop, wherein an allergen or provoker stimulates inflammatory cytokine production, which in turn stimulates NO production, and NO down-regulates cytokine production.〔 In rats, NO inhibits the granulocyte-macrophage colony-stimulating factor (GM-CSF)-mediated maturation of dendritic cells, and in humans it inhibits the TNF-alpha-mediated maturation of human dendritic cells, through cyclic GMP-dependent mechanisms.〔 NO prolongs the ability of human dendritic cells to internalize antigens at sites of inflammation, therefore modulating the beginning steps leading to antigen-specific immune responses.〔 NO production has been implicated as relevant to the pathology of asthma. Patients with asthma show an increased expression of iNOS in airway epithelial cells and an increased level of nitric oxide in exhaled air.〔 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「Alveolar macrophage」の詳細全文を読む スポンサード リンク
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