The lung must remain sterile or at least minimally contaminated, says dr. Sanjay gupta. Contamination of the lung by bacteria carries a significant risk of bacteremia, he says. The objective is to maintain the sterility of the lung without inducing inflammation.
The lung must remain sterile or at least minimally contaminated, says dr. Sanjay gupta. Contamination of the lung by bacteria carries a significant risk of bacteremia, he says. The objective is to maintain the sterility of the lung without inducing inflammation.
The lung must remain sterile or at least minimally contaminated, says dr. Sanjay gupta. Contamination of the lung by bacteria carries a significant risk of bacteremia, he says. The objective is to maintain the sterility of the lung without inducing inflammation.
Extraido de PHATOLOGY OF DOMESTIC ANIMALS VOL 2, JUBB,
KENNEDY AND PALMERS, 2007 The necessary function of gas exchange requires that the lung remain exposed to the environment. Thus, the sterility of the lung is continuously challenged by immense quantities of microorganisms and foreign material in inhaled air, and by opportunistic pathogens within droplets that are aspirated from the nonsterile upper respiratory tract. Despite this constant challenge, the lung must remain sterile or at least minimally contaminated, because excessive numbers of bacteria induce inflammation, which impedes gas exchange in the lung. dditionally, because of the tremendous blood flow through the lung, contamination of the lung by bacteria carries a significant risk of bacteremia. Thus, the lung requires a multi-layeredsystem of defense against infectious agents. The objective is to maintainthe sterility of the lung without inducing inflammation, as inflammation is detrimental to gas exchange. This is accomplished by the following: The mucus that lines the airways entraps particles and microbes, and is propelled by coughing or by ciliary beating to the pharynx, where it is swallowed. Antibody and innate defense proteins kill microbes directly, prevent them from colonizing mucosal surfaces, and/or opsonize the microbes to make them more easily ingested by phagocytes. Alveolar macrophages and newly recruited neutrophils that recognize foreign invaders, particularly in the presence of opsonins, engulf and kill these microbes without inducing inflammation. If the infection cannot be contained by these mechanisms, inflammation is triggered in an attempt to control the threat. In these situations, alveolar macrophages and airway or alveolar epithelial cells produce cytokines and other mediators that recruit neutrophils and more monocytes-macrophages to the site of invasion. Inflammatory mediators also induce the production of antibacterial proteins by epithelial cells of the airway surface and submucosal glands. But this response has the potential to do harm: inflammatory exudates impair gas exchange, leukocyte-derived enzymes and oxygen radicals cause injury to lung tissue, and repair processes may result in organization of alveolar exudates or fibrosis of alveolar septa that permanently decreases lung compliance and thickens the blood-gas barrier. The significance of these sequelae depends on the extent of lung involvement.The tremendous reserve capacity of the lung means that many animals have localized areas of pneumonia that are of no clinical significance, yet mild changes present throughout the lung can seriously compromise pulmonary function.
The inspired air may carry a variety of particulates, including infectious
agents, allergens, and inert particles. The site of particle deposition in the respiratory tract depends on their size, density, and charge. Particles larger than about 10 txm diameter are almost completely removed in the nasal cavity, mainly by impaction at sites in the nasal turbinates where the airflow changes direction. Particles that are 3-10 Ixm diameter are more likely to impact the mucosa of the trachea and bronchi, where they can be cleared by the mucociliary apparatus. In general, particles less than 5 txm have the greatest potential to reach the deep lung (terminal bronchioles and alveoli), although this is most common with smaller particles (1-2 txm).The velocity of airflow declines precipitously in the terminal airways because the total cross-sectional area increases; as a result, particle deposition in the bronchioles and alveoli results from sedimentation, diffusion, and electrostatic charge. Coughing and mucociliary clearance are the major mechanismsfor clearing of particles that become entrapped in the airways. Mucociliary clearance of particles from distal airways requires 2-6 hours, and the presence of innate defense proteins within the airway mucus, described in more detail below, probably serves to limit bacterial growth during this time. Mucociliary clearance may be as rapid as 10 mm/min in the trachea, but is much less rapid in the bronchioles.The airways are covered by a lower periciliary liquid layer (formerly known as the sol or hypophase) and a superficial mucous layer. The mucous layer contains abundant glycoproteins that are sticky and tend to trap a wide variety of particles that impact on the airway surfaces. The quality of the periciliary liquid layer is also critical for clearance of entrapped particulates, because the low viscosity of this fluid permits the cilial of the epithelial cell to beat effectively. Additionally , clearance of sputum from the larger airways by coughing requires that the periciliary liquid layer be fluid and abundant, allowing the superficial mucous layer to be easily propelled. Finally, effective ciliary function is necessary for mucociliary clearance, and requires coordinated unidirectional ciliary beating at an adequate frequency of around 15 beats per second.The regulation of this system is not well known. However, shear stress on the epithelium both increases the ciliary beating frequency and promotes epithelial secretion to maintain the quality of the liquid and mucous layer. Nitric oxide, cyclic adenosine monophosphate, and cyclic guanosine monophosphate are other regulators of ciliary beat frequency.When entrapped particles reach the nasopharynx, they have the opportunity to interact with the well-developed lymphoid tissue in the tonsils and nasopharyngeal mucosa before reaching the pharynx and being swallowed. Although this clearance of inhaled particles is normally beneficial, it is a method for the spread of agents such as Mycobacterium boris and Rhodococcus equi, and is important in the migration of helminth eggs and larvae. Mucociliary clearance may be impaired by infection of the airway epithelium with viruses, mycoplasmas, or Bordetella, exposure to cold air or ammonia, quamous metaplasia due to chronic bacterial infection or toxin exposure (cigarette smoke and environmental pollutants being the best-
characterized examples), inherited anomalies of ciliary structure or function,
or abnormal mucus production in human cystic fibrosis. The mucus covering the airway mucosa contains a rich spectrum of antimicrobial factors, which operate by several distinct mechanisms. Some cause direct injury to pathogens, such as the [3-defensins, anionic antimicrobial peptides, cathelicidins, lactoferrin, lysozyme, the complement membrane attack complex, and lactoperoxidase. Lactoferrin binds iron and makes it unavailable for use by many bacteria, while neutrophil gelatinaseassociated lipocalin- secreted by airway and alveolar epithelial cells in addition to neutrophils binds bacterial siderophores that allow pathogens to scavenge ferric iron. Other components, including immunoglobulin A and polysaccharides within the mucus, block the attachment of bacteria to mucosal surfaces. Finally, infectious agents may be opsonized by imrnunoglobulin G, the complement component C3b, and surfactant proteins A and D. Two families of antirnicrobial proteins, defensins and collectins, deserve particular mention. The defensins are a family of 3-5 kDa, cationic, arginine-rich peptides that are present in neutrophil granules, intestinal Paneth cells, and epithelial cells of the trachea and bronchi. Some defensins are constitutively expressed, while others are rapidly induced by proinflammatory cytokines, lipopolysaccharide, and other stimuli that activate nuclear factor-rd3.The defensins are able to kill bacteria, fungi, and enveloped viruses by forming pores within microbial membranes that are rich in anionic phospholipids, and may also have roles in leukocyte chemotaxis and wound healing. The collectins are a family of calciumdependent carbohydrate-binding lectin proteins that include the surfactant proteins A and D. Both of these proteins are produced by type II pneumocytes, and SP-A is also secreted by Clara cells in the bronchioles. These pulmonary collectins agglutinate and opsonize bacteria, viruses, and fungi, and also maintain suffactant homeostasis, have antioxidant activity, and bind lipopolysaccharide to regulate inflammatory responses. Alveolar macrophages are critical for defending the lung against particles that are deposited in alveoli, and also play a key role in recycling and removal of su~ctant. Their population is aintained by ongoing recruitment of blood monocytes. Alveolar macrophages are decorated by a variety of cell surface receptors that permit recognition of particles opsonized by antibody, complement, or collectins. In addition, CD14, Toll-like receptors, mannose receptors, and the scavenger receptor permit responses against bacteria that have not been previously encountered by the host. Alveolar macrophages phagocytose most opsonized particles within 2-4 hours, although the ingestion of inert particles such as carbon and silicates is much slower. Alveolar macrophages kill bacteria using reactive oxygen and nitrogen species and enzymes within their lysosomes. In addition, these cells are highly effective in promoting an inflammatory response by secreting cytokines and chemotaaic cytokines that recruit and activate neutrophils and macrophages. These newly recruited phagocytes are important in the clearance of more severe bacterial infections of the lung.
Alveolar macrophages are integral to the immune response by presenting
antigen, secreting cytokines that modulate the response, and serving as effector cells in delayed hypersensitivity reactions. However, compared to other macrophage populations, alveolar macrophages are relatively poor antigen-presenting cells.The actual physical removal of particulates from alveoli is inefficient, in contrast to their removal when deposited on the mucociliary blanket. Most particles phagocytosed by macrophages are either inactivated or sequestered.Alveolar macrophages are mainly cleared through the bronchioles on the mucociliary blanket.As the particulate load increases, as occurs in the pneumoconioses, some particles penetrate into the pulmonary interstitium by endocytosis across the type I pneumocytes, where they enter the lymph and are phagocytosed by interstitial macrophages. Particle-laden macrophages often cluster around bronchioles and blood vessels, and some eventually find their way to the local lymph nodes. In addition to the alveolar and interstitial macrophages, intravascular macrophages are present in the lung of cats, horses, ruminants, and pigs. These cells serve to remove infectious agents and other particles from the blood, and thus serve an analogous role to Kupffer cells in the liver and macrophages in splenic sinusoids. Pulmonary immune responses are initiated when inhaled antigens are taken up by dendritic cells, which inhabit the airway epithelium and migrate to bronchial lymph nodes where the antigen is presented to lymphocytes. Although bronchus-associated lymphoid tissue is often visible histologically, this structure is not present in germ-flee animals of most species and may represent a consequence of inflammation and antigenic stimulation. Finally, T lymphocytes and natural killer cells constantly survey the pulmonary milieu, and are probably most useful in defense against viruses, intracellular bacterial pathogens, and fungi. Thus, the lung is protected from inhaled bacteria by the filtering effect of the nasal cavity, innate and acquired humoral defenses, mucodliary clearance in the airways, alveolar macrophages, recruited neutrophils, and T lymphocytes and natural killer cells. These defenses can be considered in multiple layers, where most inhaled particles are removed in the nasal cavity or neutralized by innate defense proteins in the airway mucus prior to being cleared by the mucociliary apparatus. The small bronchioles seem to be a site of particular vulnerability, being poorly served by either mucociliary clearance or alveolar macrophages. Pathogens that reach the alveoli may be phagocytosed and killed by alveolar macrophages, particularly if the particles have been opsonized by complement or the surfactant proteins A and D, or by antibody ifa previous encounter with the agent has resulted in an immune response. Still greater threats invoke a suppurative inflammatory response, which may be essential Nasal cavity and sinuses to clear bacteria from the lung but also carry the risk of compromised lung function and damage to the pulmonary tissue.