Darius J. B?gli, MDCM, FRCSC, FAAP, FACS

• Associate Professor, Department of Urology,
• University of Toronto
• Associate Surgeon in Chief, Department of Surgery,
• Hospital for Sick Children,
• Toronto, Canada

Moreover antibiotic co - effective azithromycin 100mg, when one considers that these vaccines are safe and afford lifelong protection for the majority of the recipients bacterial zoonoses purchase azithromycin online from canada, some degree of public health risk may seem acceptable antimicrobial disinfectant cheap azithromycin 500mg without prescription. How such risk is determined and tolerated within a community becomes more of a sociological and ethical discussion rather than a virological question (Box 8 homeopathic antibiotics for dogs order azithromycin 100 mg with mastercard. Ensuring purity and sterility of the product is a problem inherent in the production of biological reagents on a large scale anti virus order 500mg azithromycin with visa. If the cultured cells used to propagate attenuated viruses are contaminated with unknown viruses bacteria waste buy azithromycin 100 mg free shipping, the vaccine may well contain these adventitious agents. It is estimated that 10 million to 30 million individuals received one or more doses of simian virus 40 with their poliovirus vaccine, and many developed antibodies to simian virus 40 proteins. Some concern existed that rare tumors may be linked to this inadvertent infection, but this connection has since been discounted. In another approach that relies on genome segment reassortment of influenza viruses and reoviruses, genes encoding proteins that contribute to virulence are replaced with those from related but nonpathogenic viruses. No matter which technology is applied to achieve attenuation, the genetic engineer and the classical virologist must satisfy the same fundamental requirements: isolation or construction of an infectious agent with low pathogenic potential that is, nevertheless, capable of inducing a long-lived, protective immune response. Subunit Vaccines A vaccine may consist of only a subset of viral proteins, as demonstrated by the highly successful hepatitis B vaccine. Vaccines formulated with purified components of viruses, rather than the intact particles, are called subunit vaccines. Determining which viral proteins to include in a vaccine is accomplished by selecting those that are recognized by antibodies and cytotoxic T lymphocytes; this selection can be determined by assessing the immune responses of individuals who have recovered from the disease. Therefore, the Sabin vaccine is administered as a mixture of three different strains that are representatives of poliovirus serotypes 1, 2, and 3. Shown is the derivation of the type 3 vaccine strain, called P3/Sabin (the letter P means poliovirus). The parent of P3/Sabin is P3/Leon, a virus isolated from the spinal cord of an 11-year-old boy named Leon, who died of paralytic poliomyelitis in 1937 in Los Angeles. At various intervals, viruses were cloned by limiting dilution, and the virulence of the virus was determined in monkeys. An attenuated strain was selected to be the final P3/Sabin strain included in the vaccine. Note that "revertant" does not mean that the sequence of the virus "reverts" to the sequence of the pathogenic precursor; rather, changes in other residues enable the virus to regain its potential to reproduce at wild-type virus levels. A further critical parameter is that the viral proteins must be recognized by most individuals: as humans are an outbred population, the specificities of immune recognition differ from person to person, though some antigens can be recognized by a large proportion of the human population. In principle, synthetic peptides should be the basis for an extremely safe, well-defined vaccine, in which reversion or contamination with infectious virus is impossible. To date, however, peptide vaccines have had little success, mainly because synthetic peptides are expensive to make in sufficient quantity, and the antibody response they elicit is often weak and short-lived. The attenuating mutations may lead to unexpected diversions from the natural infection and expected host response: the attenuated virus may be eliminated from the vaccinated individual before it can induce a protective response; it may infect new tissues or cells in the host with unpredictable effects; or it may initiate atypical infections. While this syndrome is most typically associated with a bacterial infection (Campylobacter jejuni), human cytomegalovirus and influenza virus have also been implicated as potential causative agents. Bacterial or viral infections (or vaccinations) can trigger a host immune response that then may cross-react with proteins present in human peripheral nerves. Vaccine side effects, whether real or not, often have a detrimental effect on public acceptance of national vaccine programs. Given that all procedures have risks, a fascinating ethical question that we must address as a society is: "How much harm can we tolerate for the global good Questions like these- which, of course, have no single answer-lie at the heart of bioethics. As only a portion of the viral genome is required for such production, there can be no contamination of the resulting vaccine with the original virus, solving a major safety problem inherent in inactivated virus vaccines. Viral proteins can be made inexpensively in large quantities by engineered organisms under conditions that simplify purification and quality control. For example, complications due to egg allergies after vaccination can be eliminated completely when influenza virus proteins are synthesized in Escherichia coli, insect cells, or yeasts. Baculoviruses, which infect insect cells in nature, can infect a large number of mammalian cell types in culture. Because this virus is nonpathogenic to humans and can be modified to express heterologous (and immunogenic) proteins from human viral pathogens, its use as a vaccine vector holds great promise. Unfortunately, most candidate subunit vaccines fail because they do not induce an immune response sufficient to protect against infection, the gold standard of any vaccine. The immune repertoire evoked by an infectious virus infection may be only partially represented in a response to a subunit vaccine. In particular, purified protein antigens rarely stimulate the appearance of mucosal antibodies, particularly IgA. To date, the single exception of a successfully engineered subunit vaccine is Flublok, in which large quantities of the hemagglutinin protein of the three most prominent influenza viruses are synthesized from baculovirus vectors in a preservative- and egg-free cell culture system. Virus-Like Particles the capsid proteins of nonenveloped and of some enveloped virus particles may self-assemble into virus-like particles. These particles have capsid-like structures that are virtually identical to those in virus particles, but unlike authentic Vaccines 273 Isolate pathogenic virus Clone genome Virulence gene Isolate virulence gene Mutate virulence gene Delete virulence gene the resulting virus is viable and immunogenic but not virulent. If the cloned genome is infectious or if mutations in plasmids can be transferred to infectious virus, it is possible to mutate viral genes systematically to find those required for producing disease. The virulence gene can then be isolated and mutated, and attenuated viruses can be constructed. Multiple point mutations or deletions are preferred to reduce or eliminate the probability of reversion to virulence. Formation of particles is critical, as purified monomeric capsid protein does not induce a protective immune response. Typically, 10 to 20 g of virus-like particles is administered in each of three doses over a 6-month period, and 95% of recipients develop antibody against the surface antigen. The hepatitis B vaccine was the first anticancer vaccine, as a portion of chronically infected individuals develop fatal liver cirrhosis and hepatocellular carcinoma. The virus-like particle vaccine effective against papillomavirus infections is among the newest vaccines developed for humans. More than 80% of sexually active women will be infected with several serotypes of human papillomavirus during their lifetime. There are numerous serotypes of this virus, but serotypes 6, 11, 16, and 18 cause 70% of cervical cancers and 90% of genital warts. Men can develop anogenital warts as well, and both sexes may develop head and neck cancers as a consequence of oral sex with an infected individual (Chapter 2). It had been known for some time that the human papillomavirus L1 capsid protein forms virus-like particles when synthesized in a variety of heterologous systems. These empty capsids proved to be exceptional inducers of a protective immune response. As a result, a quadrivalent, virus-like particle vaccine effective against the four major cancer-causing serotypes of the virus was formulated, and in 2006, the Food and Drug Administration approved this formulation as the first vaccine to be developed to prevent cervical cancer induced by a virus. As with any new vaccine, there were, and still are, attendant societal discussions about its use (Box 8. Because the empty capsids retain most of the conformational epitopes not found on purified or unstructured proteins, virus-like particle vaccines often induce durable neutralizing antibodies and other protective responses after injection. Furthermore, as the particles are completely noninfectious, inactivation with formalin or other agents is not required. This feature affords at least two additional advantages: immunogenicity is not compromised (formalin and other alkylating chemicals often alter the conformation of epitopes in inactivated vaccines), and concerns about efficiency of inactivation are avoided. Virus-like particle vaccines have proven to be particularly attractive for viruses that are propagated poorly in cell culture. The highly successful hepatitis B virus subunit vaccine comprises virus-like particles produced in yeast. In the simplest case, the plasmid encodes only the immunogenic viral protein under the control of a strong eukaryotic promoter. Remarkably, no adjuvants or special formulations are necessary to stimulate an immune response. The vaccine is approved for use in males in several countries, including the United States. It has been shown to be effective for prevention of infection by those papillomavirus strains that can cause both genital warts and anal cancer. Beyond these direct benefits, immunization of males with the human papillomavirus vaccine. Some believe that vaccination will give a false sense of security and promote promiscuity among young people, while others view the recommendations as an intrusion on parental rights. Unlike other vaccines that are mandated (as a requirement for entry into public school, for example), the papillomavirus vaccine remains elective. Consequently, individuals must make their own decisions about whether to vaccinate or not. What is not debatable is the value of vaccination, which provides protection both for the individual and for the community in which that individual resides. Ensuring that the "correct" response is made following vaccination will be a key challenge as this vaccination technology moves forward. Despite 30 years of study and enthusiasm that this vaccination strategy could be transformative for vaccine design, much remains to be investigated. Such a vaccine has the potential to present every gene product of the pathogen to the immune system. Attenuated Viral Vectors and Foreign Gene Expression Genes from a pathogenic virus can be inserted into a nonpathogenic viral vector to produce viral proteins that can immunize a host against the pathogenic virus. In principle, the vector provides the benefits of a viral infection with respect to stimulating an immune response to the exogenous proteins, but without the attendant pathogenesis associated with a virulent virus. However, any replicating viral vector has the potential to produce pathogenic side effects, particularly if injected directly into organs or the bloodstream. The immune response to such hybrid viruses is not always predictable, particularly in more vulnerable populations (children, the elderly, and immunocompromised individuals). A wide variety of systems are available for the construction of vaccinia virus recombinants that cannot replicate in mammalian cells, but that allow the efficient synthesis of cloned gene products that retain their immunogenicity. Vaccinia virus recombinants can also be used to dissect the immune response to a given protein from a pathogenic virus. Other poxviruses, including raccoonpox, canarypox, and fowlpox viruses, are possible alternatives because they are able to infect, but not propagate in, humans. Subsequent site-directed mutational analysis of the viral genes enables precise localization of these epitopes on the viral protein. Clone individual genes from pathogenic virus in vaccinia virus genome different vector expressing the same antigens, overcoming the limitations of making an immune response to the vector itself. The successful use of an oral rabies vaccine for wild animals in Europe and the United States demonstrates that recombinant vaccinia virus vaccines have considerable potential. Recombinant vaccinia virus genomes encoding the major envelope protein of rabies virus yield virus particles that are formulated in edible pellets to be spread in the wild. The pellets are designed to attract the particular animal to be immunized (for example, foxes or raccoons). The animal eats the pellet, is infected by the recombinant virus, and becomes vaccinated. As vaccinia virus infection of humans is associated with rare but serious side effects, inadvertent human infection by these wildlife vaccines poses a risk (Box 8. In this case, a woman was picking blueberries in a rural area of Pennsylvania where oral rabies vaccine baits were distributed. Her dog picked up the bait in his mouth and punctured the pouch containing the vaccine with his teeth. By four days after exposure, she noticed red blisters around her hand typical of classical vaccinia virus infection. The patient eventually recovered, but this example reminds us that "unlikely" is not the same as "impossible. Their development has been largely empirical, although as our understanding of the various regulators of immune responses increases, more-specific and -powerful adjuvants are being discovered and employed. Vaccine researchers can optimize a vaccine by using different combinations of adjuvant and immunogen to induce a protective immune response. Adjuvants act by stimulating early intrinsic and innate defense signals, which then shape subsequent adaptive responses. These immunostimulators function in at least three distinct ways: by presenting antigens as particles, by sequestering antigen at the site of inoculation, and by directly stimulating the intrinsic and innate immune responses. The latter occurs when adjuvants mimic or induce cellular damage or alter homeostasis (sometimes called "danger" signals), or when they engage intrinsic cellular defense receptors. Some adjuvants, like alum (microparticulate aluminum hydroxide gel), are widely used for human vaccines such as the papillomavirus, hepatitis A, and hepatitis B vaccines. This adjuvant is extremely potent, but causes extensive tissue damage and toxicity. Less toxic derivatives, along with saponins and linear polymers of clustered hydrophobic and hydrophilic monomers, are promising and far safer alternatives. Transgenic plants expressing viral antigens can be developed, or plant viruses with genomes encoding immunogenic proteins can be used to infect food plants. Oral vaccination, by whatever methodology, is not always possible, because the enzymes of the oral cavity, coupled with the high acidity of the alimentary tract, destroy many vaccines. Delivery and Formulation Delivery by injection has many disadvantages, and therefore improvement of the administration of vaccines is an important goal of manufacturers.

It is also likely that deposition of atmospheric particles such as tobacco smoke in this area causes some of the earliest changes in chronic bronchitis virus reproduction buy azithromycin once a day. The sharp crystals puncture lysosomal membranes antibiotic resistance nice proven azithromycin 500mg, resulting in intracellular lysosomal enzyme release and cell death infection remedies purchase 250 mg azithromycin overnight delivery. Chemotactic factors released from the dying macrophage cause fibroblast migration and collagen synthesis in the region antibiotic resistant upper respiratory infection discount azithromycin online visa. Their death stimulates additional fibroblast migration and additional collagen synthesis (see the accompanying figure) antibiotics for pimples acne azithromycin 100mg without a prescription. The end result is that the alveolar macrophage now has localized and concentrated silica or asbestos particles in a region of the lung in association with the development of pulmonary fibrosis antibiotics for neck acne buy azithromycin 100 mg with amex, a disease associated with reduced lung compliance, impaired gas exchange, and increased work of breathing. It can be taken up into the mucociliary clearance system, it can die within the alveolus and be phagocytized by other alveolar macrophages, or it can migrate into lymphoid tissue or the lung interstitium. Epithelial cells are also damaged, and they release additional inflammatory cytokines. Alveolar macrophages, lymphocytes, and neutrophils are the cells mainly responsible for the development of alveolitis. In the process of fibrosis (right side) following the inflammatory process, reparation, and fibrosis develop. These lymphoid structures are found throughout the respiratory tract in different anatomic locations. Because there is regional variation in inhaled particle deposition, each lymphoid tissue plays an important and unique role in the overall defense of the lung. Regional Lymph Nodes of the Lung the lymph nodes draining the lung are part of the mediastinal network, which drains the head and neck, the lungs, and the esophagus. The peribronchial and hilar lymph nodes are the prominent nodes in the local lung region; less prominent are the intrapulmonary nodes in the pleura and interlobar septal areas. Lymph nodes in these areas have the encapsulated organization typical of lymph nodes in other areas of the body, including the cortex, paracortex, and medulla. When activated, a germinal center is apparent in B cells and plasma cells in the cortical follicles and medullary cords, and in T cells in the paracortical areas between the follicles. In addition to being the site of antigen presentation via lymph drainage, regional lymph nodes are the sites to receive cancer cells. Thus these mediastinal nodes have significant diagnostic importance for lung cancer. In contrast to lymph nodes, these tissues are not encapsulated and are composed mainly of aggregates or clusters of lymphocytes residing in submucosal regions. Lymphoepithelium lacks ciliated epithelial cells, which results in a break in the mucociliary clearance system. IgA, and a particular form of IgA known as secretory IgA, is especially important in the nasopharynx and upper airways. Secretory IgA is composed of two IgA molecules (a dimer) joined by a polypeptide that contains an extra glycoprotein called the secretory component. Secretory IgA is synthesized locally in submucosal areas by plasma cells and secreted in a dimer form linked by a J-chain. The poly Ig receptor aids in the pinocytosis of the dimer into the epithelial cell and its eventual secretion into the airway lumen. The secretory component contains five Ig-like domains and is linked to dimeric IgA (thick black line) between its fifth domain and one of the IgA heavy chains. B, Secretory IgA is formed during transport through mucous membrane epithelial cells. Dimeric IgA binds to a poly Ig receptor on the basolateral membrane of an epithelial cell and is internalized by receptor-mediated endocytosis. After transport of the receptor-IgA complex to the luminal surface, the poly Ig receptor is enzymatically cleaved, releasing the secretory component bound to the dimeric IgA. The secretory piece stays attached to the IgA complex in the airway and aids in its protection from proteolytic cleavage in the lumen. Secretory IgA binds to antigens including viruses and bacteria and prevents their attachment to epithelial cells. The IgA also agglutinates microorganisms, which makes them more easily cleared by mucociliary transport. Synthesized locally, IgG neutralizes viruses, is an opsonin (a macromolecular coat around bacteria) for macrophage handling of bacteria, agglutinates particles, activates complement, and in the presence of complement causes lysis of Gram-negative bacteria. Once triggered, however, it is similar to the response in any other systemic organ. Under normal circumstances, bacteria such as Streptococcus pneumoniae that commonly come into contact with the upper respiratory system. However, if the bacteria elude these first-line defenses, an inflammatory response develops. These responses take 1 to 2 weeks to develop fully before a resolution of the pneumonia occurs. A typical inflammatory response to a bacterial or viral pneumonia is initially dominated by polymorphonuclear leukocytes and if it persists, a more mononuclear cell infiltrate. As with other organ systems, a transient population of bloodborne phagocytic cells (polymorphonuclear leukocytes and macrophages) resides in local vessels and is on the ready to emigrate into sites of injury. The first inflammatory cells to respond to the injury via chemotactic mechanisms, usually within 4 to 12 hours, are the polymorphonuclear leukocytes, and if the injury persists, they are followed by macrophages within 24 to 72 hours. Under circumstances in which the bacteria or other inciting agent persists and is hard to phagocytize, a granulomatous response occurs. A granulomatous response is associated with diseases such as silicosis, sarcoidosis, and the hypersensitivity lung diseases. Whereas the sequela of many acute bacterial and viral pneumonias is resolution to normal tissue, a common sequela of the chronic granulomatous type of response is scar formation. Extensive injury and cell death (necrosis) occur during the granulomatous response; as a result, the body lays down collagen to form scar tissue, which in essence "sews" up the hole left by the necrotic tissue. It replaces normal functioning tissue and therefore imparts a dysfunctional state in affected areas. Thus if 10% of the lung scars, technically speaking it may lose 10% of its functional capacity, not taking into account compensatory mechanisms. Chronic lung injury often develops after many years of exposure to these foreign materials. Excessive mucus production stresses the mucociliary transport system and stimulates the cough reflex that helps remove these secretions. Cystic fibrosis is an autosomal recessive disease characterized by thick, tenacious, dehydrated airway secretions. In addition, in cystic fibrosis there is proliferation of goblet cells and hypertrophy of submucosal glands secondary to irritation and/or abnormalities in surface liquid. Bronchial secretions in normal individuals owe their viscoelastic properties to the size, length, coiling, and cross-linking of the mucus glycoproteins, resulting in flexible elastic fibers. Antibodies neutralize and eliminate bacteria by several mechanisms, whereas T-cell responses stimulate B-cell antibody responses, macrophage activation, and inflammation. Secretions from individuals with asthma have the highest viscosity of mucus in any disease; on occasion, entire mucus casts of a lobe have been expectorated. Many processes that result in abnormal ciliary beating are associated with abnormal clearance. Ciliary beating is decreased by hypoxia, repeated exposure to the gas phases of tobacco smoke, very dry air, inflammation, and pollution, particularly of ozone. Immotile cilia syndrome is associated with abnormal ciliary microstructure throughout the body and consequently cilia that do not beat. In an allergic response, an antibody synthesis switchover response occurs and IgE, instead of IgA, becomes the predominant antibody synthesized to the allergen. The secreted IgE molecules bind to IgE-specific Fc receptors on mast cells and blood basophils. Upon a second exposure to the allergen, the bound IgE is cross-linked, triggering the release of pharmacologically active mediators (red) from mast cells and basophils. The mediators cause smooth-muscle contraction, increased vascular permeability, and vasodilation. Symptoms of wheezing, cough, and shortness of breath occur within minutes, and locally there is intense eosinophilia and airway edema. Resolution of the inflammatory response can occur spontaneously or in response to therapy (antiinflammatory drugs). Low-grade inflammation may, however, persist and can result in permanent changes in airway structure referred to as airway remodeling. In the past asthma was treated with bronchodilators; when the role of inflammation was recognized, treatment with antiinflammatory drugs became first line. These monoclonal antibodies offer opportunities for targeted therapies tailored to the needs of individuals, especially individuals with difficult-tocontrol or severe asthma. This is especially noteworthy because chemotherapeutic agents have for the most part been unsuccessful in treating these cancers. These diseases are known as hypersensitivity lung diseases and are associated with an altered immune response to the inciting agent. Only a small percentage of exposed individuals contract the disease, which is caused by the immune response to the agent, and not by the agent itself. It is not a typical allergic response, because the symptoms usually occur 4 to 6 hours after exposure, in contrast to the immediate type of response to allergens; however, some individuals can also have an allergic response. Also, the lesion is not dominated by eosinophils but consists of a polymorphonuclear cell response or a granulomatous-type response followed by pulmonary fibrosis. Pulmonary complications are common in chronic systemic diseases with possible autoimmune etiologies, including rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel diseases. It is not clear why this association exists, but it may be due to a dysregulation of immune responses that initiates a local pulmonary type of autoimmune disease. It is also associated with an intense glomerulonephritis where the disease is thought to have been initiated. The most common inherited immunoglobulin deficiency is selective IgA deficiency, with a prevalence of 1 in 800 births. Although the deficiency is not associated with any specific disease, individuals with the deficiency have a high rate of chronic lung disease, illustrating the importance of this antibody in host defense in the respiratory tract. The three major components of lung defense against inhaled particles and other inhaled materials are mucociliary transport in the larger airways, phagocytic and inflammatory cells, and a specialized mucosal immune system. The three components of mucociliary transport are periciliary fluid, mucus, and the cilia. The depth of the periciliary fluid layer is maintained by the balance between chloride secretion and sodium absorption and is essential to normal ciliary beating. Mucus is a complex macromolecule composed of glycoproteins, proteins, electrolytes, and water. The viscoelastic properties of mucus are due to the size, length, coiling, and cross-linking of the mucus glycoproteins. Three cell types produce mucus: surface secretory cells, tracheobronchial glands, and Clara cells. Pulmonary alveolar macrophages and dendritic cells are mononuclear phagocytic cells that scavenge particles and bacteria in the airways and alveoli. Polymorphonuclear leukocytes are important in lung defense against established bacterial infection. Lymphocytes and their products (B lymphocytes and humoral immunity; T lymphocytes and cell-mediated immunity) are the important components of adaptive immunity. Allergic diseases are characterized by a switchover response (IgE instead of IgA). Describe the pathology of the lung in individuals with chronic bronchitis secondary to smoking. How does macrophage phagocytosis of asbestos differ from the usual macrophage processing of microorganisms Explain how mucosa-associated lymphoid tissues differ from the systemic immune system and lymph nodes. Primary ciliary dyskinesia: an update on clinical aspects, genetics, diagnosis, and future treatment strategies. Explain fetal circulation and the changes that occur during and immediately after birth. Explain the circulatory and ventilatory changes associated with altitude and the physiologic components of acclimatization. The lung can adapt to a number of special environments and special circumstances, some of which are described here. During exercise, energy metabolism is increased through muscle contraction and the conversion of glucose to chemical energy during moderate exercise and the generation of lactic acid during strenuous exercise. With maximal exercise, a fit young man can achieve an oxygen consumption of 4 L/min with a minute volume of 120 L/min, almost 15 times resting levels, and a cardiac output that increases only 4 to 6 times above resting level. As a result, in normal individuals, the cardiovascular system and not the respiratory system is the rate-limiting factor in exercise. Work of breathing is also increased during exercise secondary to increases in both lung and chest wall elastic recoil and increases in airway resistance. Larger tidal volumes result in higher lung volumes, and both the lung and the chest wall become less compliant at these higher lung volumes, resulting in increased work to overcome the lung and chest wall elastic recoil. In addition, the airway resistance component of work of breathing increases with the higher flow rates generated during exercise (Table 12. These normal changes in work of breathing are exaggerated in individuals with abnormalities in pulmonary mechanics due to airway obstruction or to changes in lung compliance or in oxygenation and can result in exercise limitation.

Mechanism of Hypoxic Pulmonary Vasoconstriction the mechanism of hypoxic pulmonary vasoconstriction is not completely under~ stood antimicrobial nose spray generic 100 mg azithromycin with amex. Connections to the central nervous system are not necessary: An isolated antibiotics fragile x order azithromycin 100mg with mastercard, excised lung infection blood pressure cheap 250 mg azithromycin, perfused with blood by a mechanical pump with a constant output antibiotics for dogs gum infection cheap azithromycin 500mg without prescription, exhibits an increased perfusion pressure when ventilated with hypoxic gas mixtures antibiotics for sinus infection penicillin azithromycin 100 mg fast delivery. Thus best antibiotic for uti yahoo answers azithromycin 500mg on-line, it is not surprising that hypoxic pulmonary vasoconstriction persists in human patients who had received hean~lung transplants. Hypoxia may cause the release of a vasoactive substance from the pulmonary parenchyma or mast cells in the area. Histamine, serotonin, catecholamines, and prostaglandins have all been suggested as the mediator substance, but none appears to completely mimic the response. More recent studies have strongly indicated that hypoxia acts directly on pulmonary vas~ cular smooth muscle to produce hypoxic pulmonary vasoconstriction. Hypoxia inhibits an outward potassium current, which causes pulmonary vascular smooth muscle cells to depolarize, allowing calcium to enter the cells. The potassium channel appears to be open when it is oxidized and closed when it is reduced. At first thought, the location of the vasoconstriction seems difficult to explain. The P~ of the blood inside the pulmonary arterioles is a function of the P02 of the pulmonary arteries that supply those arterioles and should not be decreased. If the P~s of the alveoli surrounding the pulmonary arteriole decrease, then the smooth muscle in the arterioles will be exposed to decreased P~s outside the vessels, causing them to constrict. The problem with hypoxic pulmonary vasoconstriction is that it is not a very strong response because there is so little smooth muscle in the pulmonary vasculature. B: Perfusion of a hypoventilated alveolus results in blood with a decreased P0:2 and an increased P entering the left atrium. D: this diverts blood flow away from the hypoventilated alveolus to better-ventilated alveoli, thus helping to maintain V/Q matching. In hypoxia of the whole lung, such as might be encountered at high altitude (see Chapter 11) or in hypoventilation, hypoxic pulmonary vasoconstriction occurs throughout the lung. Even this may be useful in increasing gas exchange because gready increasing the pulmonary artery pressure recruits many previously unperfused pulmonary capillaries. This increases the surface area available for gas diffusion (see Chapter 6) and improves the matching of ventilation and perfusion, as will be discussed in the next chapter. On the other hand, such a whole-lung hypoxic pulmonary vasoconstriction gready increases the workload on the right ventricle, and the high pulmonary artery pressure may overwhelm hypoxic pulmonary vasoconstriction in some parts of the lung, increase the capillary hydrostatic pressure in those vessels, and lead to pulmonary edema see the next section of this chapter). The mechanism of hypoxic pulmonary vasoconstriction has been controversial, but as noted above many researchers currendy believe that inhibition of oxygensensitive voltage-gated potassium ion channels depolarizes smooth muscle cells in small branches of the pulmonary artery. This activates voltage-gated calcium ion channels in the smooth muscle cells, allowing influx of calcium ions, which causes the smooth muscle to contract and the vessels to constrict. Alveolar hypercapnia (high carbon dioxide) also causes pulmonary vasoconstriction. It is not dear whether this occurs by the same mechanism as that of hypoxic pulmonary vasoconstriction. Positive-pressure ventilation decreases right ventricular preload by increasing right atrial pressure, which decreases the pressure difference for venous return; and by increasing intrathoracic pressure, which compresses the great veins and restricts venous return. Also, pulmonary capillaries may be derecruited as venous return is decreased by compression of the great veins. Positive intrapleural pressure also compresses the e:xtraalveolar vessels, which decreases their transmural pressure and compresses them, increasing the resistance to blood flow. Positive alveolar pressures, combined with decreased venous return and right ventricular output, would likely introduce or increase zone 1, which is alveolar dead space, and move the border between zones 2 and 3 to lower. This pathologic condition may be caused by one or more physiologic abnormalities, but the result is inevitably impaired gas transfer. As the edema fluid builds up, first in the interstitium and later in alveoli, diffusion of gases-particularly oxygendecreases (see Chapter 6). The capillary endothelium is much more permeable to water and solutes than is the alveolar epithelium. Edema fluid therefore accumulates in the interstitium before it accumulates in the alveoli. Illustration of the factors affecting liquid movement from the pulmonary capillaries. The pulmonary lymphatic vessels are mainly located in the extraalveolar interstitium. The volume of lymph flow from the human lung is now believed to be as great as that from other organs under normal circumstances, and it is capable of increasing as much as 10-fold under pathologic conditions. It is only when this large safety factor is overwhelmed that pulmonary edema occurs. Conditions That May Lead to Pulmonary Edema the Starling equation provides a useful method of categorizing most of the potential clinical causes of pulmonary edema (Table 4-3). The pulmonary capillary hydrostatic pressure often increases secondary to problems in the left side ofthe circulation, such as infarction ofthe left ventricle, left ventricular failure, or mitral stenosis. As left atrial pressure and pulmonary venous pressure rise because of accumulating blood, the pulmonary capillary hydrostatic pressure also increases. Other causes of elevated pulmonary capillary hydrostatic pressure include overzealous administration of intravenous fluids by the physician and diseases that occlude the pulmonary veins. These include forced inspiration against an upper airway obstruction and potential actions of the physician, such as rapid evacuation of chest fluids or reduction of pneumothorax. Note that as fluid accumulates in the interstitium, the interstitial hydrostatic pressure increases, which helps limit further fluid extravasation. Plasma colloid osmotic pressure, normally in the range of 25 to 28 mm Hg, falls in hypoproteinemia or over admin~ isttation of intravenous solutions. The causes ofthe edema formation in these conditions are not known, although high~altitude pulmonary edema may be partly caused by high pulmonary artery pressures secondary to the hypoxic pulmonary vasoconstriction. Pulmonary arteries are more distensible and because their intravascular pressures are lower, more compressible than systemic arteries. His mean pulmonary artery pressure and pulmonary capillary wedge pressure (~left atrial pressure) determined using o Swon-Ganz catheter, ore 15 and 5 mm Hg, respectively. If his cardiac output is 5 Umin, calculate his pulmonary vascular resistance and systemic vascular resistance. Which of the following situations would be expected to decrease pulmonary vascular resistance Which ofthe following situations would be expected to lead to on increased amount of the lung under zone 7 conditions Which of the following circumstances might be expected to contribute to the formation of pulmonary edema At rest, his hean rate is 105/min, blood pressure is 120/90, and his respiratory rate is increased at 20/min. The patient does not have dyspnea (the feeling of difficult breathing or "shortness of breath") at rest and his blood pressure is within the normal range. His heart rate at rest is slightly above the normal range (50-100/min; ttlehycmvlitt), and his respiratory rate is high (normally 12-15/min; ttlehypnea). He had a left ventricular myocardial infarction 3 months ago and the damaged hean muscle has been replaced with scar tissue that cannot contract. Although his left ventricle can generate a sufficient stroke volume at rest, it cannot match the increased right ventricular output during exercise, leading to increased left atrial pressure. Because there are no valves between the left atrium and the pulmonary veins and capillaries, pulmonary capillary hydrostatic pressure increases. Filtration of fluid from the capillaries into the pulmonary interstitium increases sufficiently to exceed the ability of the pulmonary lymphatic drainage to remove it, resulting in interstitial edema and then alveolar edema. Interstitial and alveolar edema increase the alveolar-capillary barrier for gas diffusion. This is particularly a problem for oxygen diffusion, as will be discussed in Chapter 6. Stretch receptors in the pulmonary circulation U receptors) respond to pulmonary vascular congestion and the arterial cbemorccepton respond to low arterial Pa:z, both contributing to the sensation of dyspnea, as will be discussed in Chapter 9. He breathes more easily in the upright position because the edema fluid collects in lower regions of the lungs, allowing better gas exchange in upper parts of the lungs. Inhaled nitric oxide alters the distribution of blood flow in the healthy human lung, suggesting active: hypoxic pulmonary vasoconstriction in normoxia. InRuence of pulmonary arterial and left atrial pres-sure on pulmonary vascular resistance. Distribution of blood flow in isolated lung: relation to vascular and alveolar pressures. Ill- Describes the methods used to determine the uniformity ofthe distribution ofthe inspired gas and pulmonary blood flow. Gas exchange between the alveoli and the pulmonary capillary blood occurs by diffusion, as will be discussed in the next chapter. Diffusion of oxygen and carbon dioxide occurs passivdy; according to their concentration differences across the alveolar-capillary barrier. These concentration differences must be maintained by ventilation of the alveoli and perfusion of the pulmonary capillaries. Similarly, the mixed venous blood brings carbon dioxide into the lung and takes up alveolar oxygen. Alveolar ventilation is normally about 4 to 6 Umin and pulmonary blood flow (which is equal to cardiac output) has a similar range, and so the V/Q for the whole lung is in the range of0. For instance, suppose that all 5 Umin of the cardiac output went to the left lung and all5 Umin of alveolar ventilation went to the right lung. Similarly, carbon dioxide is delivered to the alveolus in the mixed venous blood and diffuses into the alveolus in the pulmonary capillary. As will be discussed in Chapter 6, at resting cardiac outputs the diffusion of both oxygen and carbon dioxide is normally limited by pulmonary perfusion. Thus, the alveolar partial pres~ sures ofboth oxygen and carbon dioxide are determined by the V/Q. If the V/Q in an alveolar~capillary unit increases, the delivery of oxygen relative to its removal will increase, as will the removal of carbon dioxide relative to its ddivery. If the V/Q in an alveolar~capillary unit decreases, the removal of oxygen rdative to its delivery will increase and the delivery of carbon dioxide relative to its removal will increase. Inspired air enters the alveolus with a P02 of about 150 mm Hg and a Pc02 of nearly 0 mm Hg. Mixed venous blood enters the pulmonary capillary with a P02 of about 40 mm Hg and a Pc02 of about 45 mm Hg. The partial pressure difference for oxygen diffusion from alveolus to pulmonary capillary is thus about 100 to 40 mm Hg, or 60 mm Hg; the partial pressure difference for C02 diffusion from pulmonary capillary to alveolus is only about 45 to 40, or 5 mm Hg. With time, the air trapped in the alveolus equilibrates by diffusion with the gas dis~ solved in the mixed venous blood entering the alveolar-capillary unit. The blood flow to unit Cis blocked by a pulmonary embolus, and unit Cis th~ fore completdy unperfused. Because no oxygen can diffuse from the alveolus into pulmonary capillary blood and because no carbon dioxide can enter the alveolus from the blood, the P02 of the alveolus is approximatdy 150 mm Hg and its Pc02 is appro:ximatdy zero. That is, the gas composition of this unper~ fused alveolus is the same as that of inspired air. If unit C were unperfused because its alveolar pressure exceeded its pre-capillary pressure (rather than because of an embolus), then it would also correspond to part of zone 1. This simple 02 ~C0 2 diagram can be modified to include correction lines for other factors, such as the respiratory exchange ratios of the alveoli and the blood or the dead space. The position of the V/Q ratio line is altered if the partial pressures of the inspired gas or mixed venous blood are altered. Uneven resistance to airflow may be a result of collapse of airways, as seen in emphysema; bronchocon~ striction, as in asthma; decreased lumen diameter due to inflammation, as in bron~ chitis; obstruction by mucus, as in asthma or chronic bronchitis; or compression by tumors or edema. Uneven compliance may be a result of flbrosis, regional variations in surfactant production, pulmonary vascular congestion or edema, emphysema, diffuse or regional atdectasis, pneumothorax, or compression by tumors or cysts. Multiple inert gas technique V/Q =ventilation-perfusion ratio; (A-a) 0 92 =alveolar-arterial oxygen difference; (a-A) Dc<>:z =arterial alveolar carbon dioxide difference. Nonuniform perfusion of the lung can be caused by embolization or thrombo~ sis; compression of pulmonary vessds by high alveolar pressures, tumors, exudates, edema, pneumothorax, or hydrothorax; destruction or occlusion of pulmonary ves~ sds by various disease processes; pulmonary vascular hypotension; or collapse or overexpansion of alveoli. As already noted in Chapters 3 and 4, gravity, local factors, and regional differences in intrapleural pressure cause a degree of nonuniformity in the distribution ofventilation and perfusion in normal lungs. The methods used for testing for nonuniform ventilation, nonuniform perfu~ sion, and ventilation-perfusion mismatch an: summarized in Table 5-1. Testing for Nonuniform Distribution of Inspired Gas Several methods can be used to demonstrate an abnormal distribution of ventila~ tion in a patient. In this test, the subject breathes normally through a one-way valve from a bag of 100% oxygen, and the expired nitrogen concentration is monitored over a number of breaths. The rate of decrease of the expired end-tidal nitrogen concentration depends on several factors. Nonethdess, subjects with a normal distribution of airways resistance will reduce their expired end-tidal nitrogen concentration to less than 2. Subjects breathing normally who take more than 7 minutes to reach an alveolar nitrogen concentration ofless than 2. After a short period of rdativdy rapid nitrogen washout, a long period of extremdy slow nitrogen washout occurs, indicating a population of poorly ventilated "slow alveoli. Expired nitrogen concentration versus number of breaths during a nitrogen washout.

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