Respiratory System, Mediastinum, and Pleurae


Respiratory System, Mediastinum, and Pleurae

Diseases of the respiratory system (respiratory apparatus) are some of the leading causes of morbidity and mortality in animals and a major source of economic losses. Thus veterinarians are routinely called to diagnose, treat, and implement health management practices to reduce the impact of these diseases. In companion animals, diseases of the respiratory tract are also common and, although of little economic significance, are important to the health of the animals and thus to clinicians and owners.

Structure and Function

To facilitate the understanding of the structure and function, it is convenient to arbitrarily divide the respiratory system into conducting, transitional, and gas exchange systems (Fig. 9-1). The conducting system includes nostrils, nasal cavity, paranasal sinuses, nasopharynx, larynx, trachea, and extrapulmonary and intrapulmonary bronchi, all of which are largely lined by pseudostratified, ciliated columnar cells plus a variable proportion of secretory goblet (mucous) and serous cells (Figs. 9-2 and 9-3 and Web Fig. 9-1). The transitional system of the respiratory tract is composed of bronchioles, which serve as a transition zone between the conducting system (ciliated) and the gas exchange (alveolar) system (see Fig. 9-1). The disappearance of cilia in the transitional system is not abrupt; the ciliated cells in the proximal bronchiolar region become scarce and progressively attenuated, until the point where distal bronchioles no longer have ciliated cells. Normal bronchioles also lack goblet cells, but instead have other types of secretory cells, notably Clara and neuroendocrine cells. Clara cells, also referred to as secretory bronchiolar cells, contain numerous biosynthetic organelles that play an active role in detoxification of xenobiotics (foreign substances), similar to the role of hepatocytes (Fig. 9-4). Clara cells are also critical stem cells in the repair and remodeling of not only the bronchioles, but of most of the respiratory tract. In addition, Clara cells contribute to the innate immunity of the lung by secreting protective proteins (collectins) and pulmonary surfactant (Fig. 9-4, B). In carnivores and monkeys, and to a much lesser extent in horses and humans, the terminal portions of bronchioles are not only lined by cuboidal epithelium but also by segments of alveolar capillaries. These unique bronchioloalveolar structures are known as respiratory bronchioles (Fig. 9-5; also see Fig. 9-1). The gas exchange system of the respiratory tract in all mammals is formed by alveolar ducts and millions of alveoli (Fig. 9-6; also see Fig. 9-1). The surface of the alveoli is lined by two distinct types of epithelial cells known as type I pneumonocytes (membranous) and type II pneumonocytes (granular) (Fig. 9-7).

All three—the conducting, transitional, and exchange systems of the respiratory system—are vulnerable to injury because of constant exposure to a myriad of microbes, particles and fibers, and toxic gases and vapors present in the air. Vulnerability of the respiratory system to aerogenous (airborne) injury is primarily because of (1) the extensive area of the alveoli, which are the interface between the blood in alveolar capillaries and inspired air; (2) the large volume of air passing continuously into the lungs; and (3) the high concentration of noxious elements that can be present in the air (Table 9-1). For humans, it has been estimated that the surface of the pulmonary alveoli is approximately 200 m2, roughly the area of a tennis court. It has also been estimated that the volume of air reaching the human lung every day is around 9000 L. The surface of the equine lung is estimated to be around 2000 m2.

Lungs are also susceptible to blood-borne (hematogenous) microbes, toxins, and emboli. This fact is not surprising because the entire cardiac output of the right ventricle goes into the lungs, and approximately 9% of the total blood volume is within the pulmonary vasculature. The pulmonary capillary bed is the largest in the body, with a surface area of 70 m2 in the adult human; this area is equivalent to a length of 2400 km of capillaries, with 1 mL of blood occupying up to 16 km of capillary bed.

Normal Flora of the Respiratory System

The respiratory system has its own normal flora (microbiota), as does any other body system in contact with the external environment. If a sterile swab is passed deep into the nasal cavity of any healthy animal and cultured for microbes, yeasts, and fungi, many species of bacteria are recovered, such as Mannheimia (Pasteurella) haemolytica in cattle; Pasteurella multocida in cats, cattle, and pigs; and Bordetella bronchiseptica in dogs and pigs. The organisms that constitute the normal flora of the respiratory tract are restricted to the most proximal (rostral) region of the conducting system (nasal cavity, pharynx, and larynx). The thoracic portions of the trachea, bronchi, and lungs are considered to be essentially sterile. The types of bacteria present in the nasal flora vary considerably among animal species and in different geographic regions of the world. Some bacteria present in the nasal flora are pathogens that can cause important respiratory infections. For instance, Mannheimia (Pasteurella) haemolytica is part of the bovine nasal flora, yet this bacterium causes a devastating disease in cattle—pneumonic Mannheimiosis (shipping fever). Experimental studies have established that microorganisms from the nasal flora are continuously carried into the lungs via tracheal air. In spite of this constant bacterial bombardment from the nasal flora and from contaminated air, normal lungs remain sterile because of their remarkably effective defense mechanisms.

Portals of Entry into the Respiratory System

Microbes, toxins, and pneumotoxicants can gain access into the respiratory system by the following routes (also see Tables 9-1 and 9-2):

1. Aerogenous—Pathogens, such as bacteria, mycoplasmas, and viruses, along with toxic gases and foreign particles, including food, can gain access to the respiratory system via inspired air. This is the most common route in the transmission of most respiratory infections in domestic animals.

2. Hematogenous—Some viruses, bacteria, parasites, and toxins can enter the respiratory system via the circulating blood. This portal of entry is commonly seen in septicemias, bacteremias, and protozoa and viruses that target endothelial cells. Also, circulating leukocytes may release infectious organisms such as retroviruses and Listeria monocytogenes while traveling through the lungs.

3. Direct extension—In some instances, pathogenic organisms can also reach the pleura and lungs through penetrating injuries, such as gunshot wounds, migrating awns, or bites, or by direct extension from a ruptured esophagus or perforated diaphragm.

Defense Mechanisms of the Respiratory System

It is axiomatic that a particle, microbe, or toxic gas must first gain entry to a vulnerable region of the respiratory system before it can induce an adaptive immune response or have a pathologic effect. The characteristics of size, shape, dispersal, and deposition of particles present in inspired air are studied in aerobiology. It is important to recognize the difference between deposition, clearance, and retention of inhaled particles. Deposition is the process by which particles of various sizes and shapes are trapped within specific regions of the respiratory tract. Clearance is the process by which deposited particles are destroyed, neutralized, or removed from the mucosal surfaces. The difference between what is deposited and what is cleared from the respiratory tract is referred to as retention. The main mechanisms involved in clearance are sneezing, coughing, mucociliary transport, and phagocytosis (Table 9-3). Abnormal retention of particles resulting from increased deposition, decreased clearance, or a combination of both is the underlying pathogenetic mechanism in many pulmonary diseases (Fig. 9-8).

The anatomic configuration of the nasal cavity and bronchi plays a unique role in preventing or reducing the penetration of noxious material into the lungs, especially into the alveoli, which is the most vulnerable portion of the respiratory system. The narrow nasal meatuses and the coiled arrangement of the nasal conchae generate enormous turbulences of airflow and as a result, physical forces are created that forcefully impact particles larger than 10 µm onto the surface of the nasal mucosa (Fig. 9-9). Although particles smaller than 10 µm could escape trapping in the nasal cavity, these medium-sized particles meet a second barrier at the tracheal and bronchial bifurcations. Here, abrupt changes in the direction of air (inertia), which occurs at the branching of major airways, cause particles in the 2- to 10-µm size range to collide with the surface of bronchial mucosa (see Fig. 9-1). Because the velocity of inspired air at the level of the small bronchi and bronchioles has become rather slow, inertial and centrifugal forces no longer play a significant role in the trapping of inhaled particles. Here, in the transitional (bronchiolar) and exchange (alveolar) regions, particles 2 µm or smaller may come into contact with the mucosa by means of sedimentation because of gravitation or by diffusion as a result of Brownian movement. Infective aerosols containing bacteria and viruses are within the size ranges (0.01 to 2 µm) that typically gain access to the bronchioloalveolar region.

In addition to size, other factors, such as shape, length, electrical charge, and humidity, play an important role in mucosal deposition, retention, and pathogenicity of inhaled particles. For example, particles longer than 200 µm may also reach the lower respiratory tract, provided their mean aerodynamic diameter is less than 1 µm. Asbestos is a good example of a large but slender fiber that can bypass the filtrating mechanisms by traveling parallel to the airstream. Once in the terminal bronchioles and alveoli, asbestos fibers cause asbestosis, a serious pulmonary disease in humans. In summary, the anatomic features of the nasal cavity and airways provide an effective barrier, preventing the penetration of most large particles into the lungs.

Once larger particles are trapped in the mucosa of conducting airways and small particles are deposited on the surface of the nasal, tracheal, or bronchioalveolar mucosa, it is crucial that these exogenous materials be removed to prevent or minimize injury to the respiratory system. For these purposes, the respiratory system is equipped with several defense mechanisms, all of which are provided by specialized cells operating in a remarkably well-coordinated manner.

Defense Mechanisms of the Conducting System (Nose, Trachea, and Bronchi)

Mucociliary clearance is the physical unidirectional movement and removal of deposited particles and gases dissolved in the mucus from the respiratory tract. Mucociliary clearance, also referred to as the waste disposal system, is provided by the mucociliary blanket (mucociliary escalator) and is the main defense mechanism of the conducting system (nasal cavity, trachea, and bronchi) (see Figs. 9-2 and 9-3). Mucus acts primarily as a barrier and a vehicle and is a complex mixture of water, glycoproteins, immunoglobulins, lipids, and electrolytes produced by goblet (mucous) cells, serous cells, submucosal glands, and fluid from transepithelial ion and water transport. Once serous fluid and mucus are secreted onto the surface of the respiratory mucosa, a thin, double-layer film of mucus is formed on top of the cells. The outer layer of this film is in a viscous gel phase, whereas the inner layer, which is in a fluid or sol phase, is directly in contact with cilia (see Fig. 9-3). A healthy human produces around 100 mL of mucus per day. Each ciliated cell in the conducting system has around 100 to 200 motile and chemosensory cilia (6 µm long), beating metachronously (forming a wave) at a ciliary beat frequency of approximately 1000 strokes per minute, and in a horse, for example, mucus moves longitudinally at a rate of up to 20 mm per minute. Rapid and powerful movement of cilia creates a series of waves that, in a continuous and synchronized manner, propel the mucus, exfoliated cells, and entrapped particles out of the respiratory tract to the pharynx. The mucus is finally swallowed, or when present in large amounts, it is coughed up out of the conducting system. If mucus flow were to move at the same rate in all levels of a conducting system, a “bottleneck” effect would be created in major airways as the minor but more numerous airways enter the bronchi. For this reason, the mucociliary transport in proximal (rostral) airways is physiologically faster than that of the distal (caudal) ones. Ciliary activity and mucus transport increase notably in response to stimuli such as in respiratory infections.

The mucociliary blanket of the nasal cavity, trachea, and bronchi also plays an important role in preventing injury from toxic gases. If a soluble gas contacts the mucociliary blanket, it mixes with the mucus, thus reducing the concentration of gas reaching deep into the alveoli. In other words, mucus acts as a “scavenger system,” whereby gases are solubilized and subsequently cleared from the respiratory tract via mucociliary transport. If ciliary transport is reduced (loss of cilia) or mucus production is excessive, coughing becomes an important mechanism for clearing the airways.

In addition to the mechanical barrier and physical transport provided by the mucociliary escalator, other cells closely associated with ciliated epithelium contribute to the defense mechanism of the conducting system. Among the most notable ones are the microfold (M) cells, which are modified epithelial cells covering the bronchial-associated lymphoid tissue (BALT), both of which are strategically situated at the corner of the bifurcation of bronchi and bronchioles, where inhaled particles often collide with the mucosa because of inertial forces. From here, inhaled particles and soluble antigens are phagocytosed and transported by macrophages, dendritic cells, and other professional antigen-presenting cells (APCs) into the BALT, thus providing a unique opportunity for B and T lymphocytes to enter into close contact with inhaled pathogenic substances. Pulmonary lymphocytes are not quiescent in the BALT but are in continual traffic to other organs and contribute to both cellular (cytotoxic, helper, suppressor T lymphocytes) and humoral immune responses. Immunoglobulin A (IgA), produced by mucosal plasma cells, and to a lesser extent, immunoglobulin G (IgG) and M (IgM) play important roles in the local immunity of the conducting system, especially with regard to preventing attachment of pathogens to the cilia. Chronic airway diseases, especially those caused by infection, such as those caused by mycoplasmas or retroviruses, are often accompanied by severe hyperplasia of the BALT.

The mucociliary clearance terminates at the pharynx, where mucus, propelled caudally from the nasal cavity and cranially from the tracheobronchial tree, is eventually swallowed and thus eliminated from the conducting system of the respiratory tract. Some respiratory pathogens, such as Rhodococcus equi, can infect the intestines after having been removed and swallowed from the respiratory tract into the alimentary system.

Defense Mechanisms of the Exchange System (Alveoli)

Alveoli lack ciliated and mucus-producing cells; thus the defense mechanism against inhaled particles in the alveolar region cannot be provided by mucociliary clearance. Instead, the main defense mechanism of alveoli (exchange system) is phagocytosis provided by the pulmonary alveolar macrophages (Fig. 9-10). These highly phagocytic cells, which are not to be confused with intravascular pulmonary macrophages, are derived largely from blood monocytes and to a much lesser extent, from a slowly dividing population of interstitial macrophages. After a temporary adaptive stage within alveolar interstitium, blood monocytes reduce their glycolytic metabolism and increase their oxidative metabolism to function in an aerobic rather than an anaerobic environment. Pulmonary alveolar macrophages contribute to the pulmonary innate and adaptive immune response rapidly attaching and phagocytosing bacteria and any other particle reaching the alveolar lumens. The number of free macrophages in the alveolar space is closely related to the number of inhaled particles reaching the lungs. This ability to increase, within hours, the number of available phagocytic cells is vital in protecting the distal lungs against foreign material, particularly when the inhaled particle load is high. Unlike that of tissue macrophages, the lifespan of alveolar macrophages in the alveoli is notably short, only a few days, and thus they are continuously being replaced by newly migrated blood monocytes.

Alveolar phagocytosis plays a prominent role in the innate defense mechanism against inhaled bacteria without the need of an inflammatory reaction. Bacteria reaching the alveoli are rapidly phagocytosed, and bactericidal enzymes present in lysosomes are discharged into the phagosome containing the bacteria (see Fig. 9-10). Except for some facultative pathogens that are resistant to intracellular killing (e.g., Mycobacterium tuberculosis, Listeria monocytogenes, Brucella abortus, and some Salmonella spp.), most bacteria reaching the lungs are rapidly destroyed by activated alveolar macrophages. Similarly, inhaled particles, such as dust, pollen, spores, carbon, or erythrocytes from intraalveolar hemorrhage, are all phagocytosed and eventually removed from alveoli by pulmonary alveolar macrophages. Most alveolar macrophages leave the alveoli by migrating toward the bronchiolar (transitional) region until the mucociliary blanket is reached. Once there, pulmonary macrophages are removed in the same way as any other particle: along the mucociliary flow to the pharynx and swallowed. In the cat, as many as 1 million macrophages per hour move out from the alveoli into the conducting system and pharynx.

Destruction and removal of inhaled microbes and particles by alveolar macrophages is a well-orchestrated mechanism that engages many cells, receptors (i.e., Toll-like receptors [TLRs]) and pulmonary secretions in the lung. The cell-to-cell interactions are complex and involve pulmonary alveolar macrophages, pneumonocytes, endothelial cells, lymphocytes, plasma cells, natural killer (NK) cells, and dendritic cells. Antibodies are also important in the protection (acquired immune response) of the respiratory tract against inhaled pathogens. IgA is the most abundant antibody in the nasal and tracheal secretions and prevents the attachment and absorption of antigens (immune exclusion). IgG and to a lesser extent IgE and IgM promote the uptake and destruction of inhaled pathogens by phagocytic cells (immune elimination). IgG is the most abundant antibody in the alveolar surface and acts primarily as an opsonizing antibody for alveolar macrophages and neutrophils. In addition to antibodies, there are several secretory products locally released into the alveoli that constitute the alveolar lining material and contribute to the pulmonary defense mechanisms. The most important of these antimicrobial products are transferrin, anionic peptides, and pulmonary surfactant (Table 9-4).


Defense Mechanisms Provided by Some Cells and Secretory Products Present in the Respiratory System

Cell/Secretory Product Action
Alveolar macrophage Phagocytosis, main line of defense against inhaled particles and microbial pathogens in the alveoli
Intravascular macrophage Phagocytosis, removal of particles, endotoxin, and microbial pathogens in the circulation
Ciliated cells Expel mucus and inhaled particles and microbial pathogens by ciliary action
Clara cells Detoxification of xenobiotics (mixed function oxidases) and protective secretions against oxidative stress and inflammation; production of surfactant
Mucus Physical barrier; traps inhaled particles and microbial pathogens and neutralizes soluble gases
Surfactant Protects alveolar walls and enhances phagocytosis
Lysozyme Antimicrobial enzyme
Transferrin and lactoferrin Inhibition and suppression of bacterial growth
α1-Antitrypsin Protects against the noxious effects of proteolytic enzymes released by phagocytic cells; also inhibits inflammation
Interferon Antiviral agent and modulator of the immune and inflammatory responses
Interleukins Chemotaxis, upregulation of adhesion molecules
Antibodies Prevent microbe attachment to cell membranes, opsonization
Complement Chemotaxis; enhances phagocytosis
Antioxidants* Prevent injury caused by superoxide anion, hydrogen peroxide, and free radicals (ROS) generated during phagocytosis, inflammation, or by inhalation of oxidant gases (ozone, nitrogen dioxide [NO2], sulfur dioxide [SO2])

*Superoxide dismutase, catalase, glutathione peroxidase, oxidant free radical scavengers (tocopherol, ascorbic acid).

To facilitate phagocytosis and discriminate between “self” and “foreign” antigens, pulmonary alveolar macrophages are furnished with a wide variety of specific receptors on their cell surfaces. Among the most important ones are Fc receptors for antibodies; complement receptors (C3b, C3a, C5a); tumor necrosis factor (TNF) receptor; and CD40 receptors, which facilitate phagocytosis and destruction of opsonized particles. TLRs recognize microbial components, and FAS receptors are involved in apoptosis and in the phagocytosis of apoptotic cells in the lung. “Scavenger receptors,” which are responsible for the recognition and uptake of foreign particulates, such as dust and fibers, are also present on pulmonary alveolar macrophages.

Defense Mechanisms Against Blood-Borne Pathogens (Intravascular Space)

Lungs are also susceptible to hematogenously borne microbes, toxins, or emboli. The hepatic (Kupffer cells) and splenic macrophages are the primary phagocytic cells responsible for removing circulating bacteria and other particles from the blood of dogs, some rodents, and humans. In contrast, the cell responsible for the removal of circulating particles, bacteria, and endotoxin from the blood of ruminants, cats, pigs, and horses is mainly the pulmonary intravascular macrophage, a distinct population of phagocytes normally residing within the pulmonary capillaries (see Fig. 9-7). In pigs, 16% of the pulmonary capillary surface is lined by pulmonary intravascular macrophages. In ruminants, 95% of intravenously injected tracer particles or bacteria are rapidly phagocytosed by these intravascular macrophages. Recent studies showed that an abnormally reduced number of Kupffer cells in diseased liver results in a compensatory increase in pulmonary intravascular macrophages, even in animal species in which these phagocytic cells are normally absent from the lung. In some abnormal conditions, such as sepsis, excessive release of cytokines by pulmonary intravascular macrophages may result in acute lung injury.

Defense Mechanisms Against Oxidant-Induced Lung Injury

Existing in an oxygen-rich environment and being the site of numerous metabolic reactions, the lungs also require an efficient defense mechanism against oxidant-induced cellular damage (oxidative stress). This form of damage is caused by inhaled oxidant gases (e.g., nitrogen dioxide, ozone, sulfur dioxide, or tobacco smoke), by xenobiotic toxic metabolites produced locally, by reaching the lungs via the bloodstream (e.g., 3-methylindole and paraquat), or by free radicals (reactive oxygen species) released by phagocytic cells during inflammation. Free radicals and reactive oxygen species (ROS) not only induce extensive pulmonary injury but also impair the defense and repair mechanisms in the lung. Oxygen and free radical scavengers, such as catalase, superoxide dismutase, ubiquinone, and vitamins E and C, are largely responsible for protecting pulmonary cells against peroxidation. These scavengers are present in alveolar and bronchiolar epithelial cells and in the extracellular spaces of the pulmonary interstitium.

In summary, the defense mechanisms are so effective in trapping, destroying, and removing bacteria that, under normal conditions, animals can be exposed to aerosols containing massive numbers of bacteria without any ill effects. If defense mechanisms are impaired, inhaled bacteria colonize and multiply in bronchi, bronchioles, and alveoli, and produce infection, which can result in fatal pneumonia. Similarly, when blood-borne pathogens, inhaled toxicants, or free radicals overwhelm the protective defense mechanisms, cells of the respiratory system are likely to be injured, often causing serious respiratory diseases.

Impairment of Defense Mechanisms in the Respiratory System

For many years, factors such as stress, viral infections, and pulmonary edema have been implicated in predisposing humans and animals to secondary bacterial pneumonia. There are many pathways by which the defense mechanisms can be impaired; only those relevant to veterinary species are discussed.

Viral Infections

Viral agents are notorious in predisposing humans and animals to secondary bacterial pneumonias by what is known as viral-bacterial synergism. A good example of this synergistic effect of combined virus-bacterial infections is documented from epidemics of humans with influenza virus in which the mortality rate has been significantly increased from secondary bacterial pneumonia. The most common viruses incriminated in predisposing animals to secondary bacterial pneumonia include influenza virus in pigs and horses; bovine herpesvirus 1 (BoHV-1), parainfluenza-3 (PI-3), and bovine respiratory syncytial virus (BRSV) in cattle; canine distemper virus in dogs; and herpesvirus and calicivirus in cats. The mechanism of the synergistic effect of viral-bacterial infections was previously believed to be the destruction of the mucociliary blanket and a concurrent reduction of mucociliary clearance, but in experimental studies, viral infections did not significantly reduce the physical removal of particles or bacteria out of the lungs. Now, it is known that 5 to 7 days after a viral infection, the mucociliary clearance and phagocytic function of pulmonary alveolar macrophages are notably impaired (see Fig. 9-8). Other mechanisms by which viruses impair defense mechanisms are multiple and remain poorly understood (Box 9-1). Immunization against viral infections in many cases prevents or reduces the synergistic effect of viruses and thus the incidence of secondary bacterial pneumonia


Immunodeficiency disorders, whether acquired or congenital, are often associated with increased susceptibility to viral, bacterial, and protozoal pneumonias. For example, humans with acquired immunodeficiency syndrome (AIDS) are notably susceptible to pneumonia caused by proliferation of Pneumocystis carinii. This ubiquitous organism, which under normal circumstances is not considered pathogenic, is also found in the pneumonic lungs of immunosuppressed pigs, foals, dogs, and rodents. Pigs infected with the porcine reproductive and respiratory syndrome (PRRS) virus frequently develop Pneumocystis carinii infection. Arabian foals born with combined immunodeficiency disease easily succumb to infectious diseases, particularly adenoviral pneumonia. Combined infections with two respiratory viruses, such as canine distemper and canine adenovirus (CAV-2), are sporadically reported in immunosuppressed puppies. Also, large doses of chemotherapeutic agents, such as steroids and alkylating agents, cause immunosuppression in dogs, cats, and other animals, increasing susceptibility to secondary viral and bacterial infections.

Other Conditions that Predispose to Secondary Bacterial Pneumonia

Uremia, endotoxemia, dehydration, starvation, hypoxia, acidosis, pulmonary edema, anesthesia, ciliary dyskinesia, and stress are only some of the many conditions that have been implicated in impairing respiratory defense mechanisms and consequently predisposing animals to develop secondary bacterial pneumonia. The mechanisms by which each of these factors suppresses pulmonary defenses are diverse and sometimes not well understood. For example, hypoxia and pulmonary edema decrease phagocytic function of pulmonary alveolar macrophages and alter the production of surfactant by type II pneumonocytes. Dehydration is thought to increase the viscosity of mucus, reducing or stopping mucociliary movement. Anesthesia induces ciliostasis, with concurrent loss of mucociliary function. Ciliary dyskinesia, an inherited defect in cilia, causes abnormal mucus transport; starvation, hypothermia, and tress can reduce humoral and cellular immune responses.

Structure and Function

Examination of the Respiratory Tract


The respiratory tract should always be examined in a systematic fashion. To determine whether negative pressure is present in the thoracic cavity, the diaphragm is punctured through the abdominal cavity before the thoracic cavity has been opened. When the diaphragm is punctured in a fresh carcass, the loss of negative pressure in the thorax causes the diaphragmatic cupola to drop back caudally toward the abdominal cavity, and at the same time, there is an audible sound caused by the inrush of air into the thorax. Lack of this movement may be an indication of advanced pneumothorax, pleural effusion, or the presence of uncollapsed lungs caused by pulmonary edema, pneumonia, fibrosis, or emphysema. In carcasses that have been dead for a long time, pulmonary air and gas produced by saprophytic bacteria leak into the pleural cavity, reducing the negative thoracic pressure and collapsing the lung.

The rib cage must be removed by cutting along the costosternal joints and along the neck of the ribs (close to the costovertebral joints) in such a way that pleural adhesions and abnormal thoracic contents can be observed and grossly quantified (e.g., 200 mL of clear, yellow fluid). The tongue, pharynx, esophagus, larynx, trachea, and thoracic viscera (lungs, heart, and thymus) should be removed as a unit (often called the pluck) and placed on the necropsy table.

The pharynx and esophagus are opened starting at the pharynx by a single cut with scissors along the dorsal midline and inspected for ulcers, foreign bodies, and neoplasms. The larynx and trachea must be examined by opening both along the dorsal midline from cranial to caudal ends and then extending the incision into the large bronchi of the caudal lung lobes. Normal tracheobronchial mucosa has a smooth and glistening pearl-colored surface with empty lumina in airways. The presence of foamy fluid in airways indicates pulmonary edema. Feed particles may suggest aspiration; however, careful examination of the mucosa is required because aspiration of ingesta from stomach or rumen into the lungs commonly takes place agonally or can be displaced into these areas when the carcass is moved.

The lungs should be examined before incision. Normal lungs typically have a homogeneous pink color (Web Fig. 9-2). External changes include the presence of rib imprints on the pleural surface when lungs fail to collapse. In addition, the lungs should be inspected for changes in color and texture and distribution of lesions. Color changes can be various shades of red, indicating hypostatic congestion, hyperemia (acute pneumonia), and hemorrhage; dark blue collapsed lobules or areas are indicative of atelectasis; pale pink to white lungs indicate notable anemia, fibrosis, or emphysema; and uniformly or patchy yellow-brown lungs indicate chronic passive congestion and pulmonary fibrosis likely secondary to chronic heart failure. Lungs from exsanguinated animals are generally paler than the normal pink color because of reduced blood in the pulmonary tissue. A covering of yellowish material on the pleural surface indicates accumulation of fibrin. Because it is impossible to describe the texture of normal lungs, experience in palpation is required to appreciate the actual texture of a normal lung. Texture is determined by gently palpating the surface and parenchyma of the lungs. Normal texture can change to firm, hard, elastic (rubbery), or crepitus (with a crackling sound or feeling). For a detailed description of lung texture, see the section on Classification of Pneumonias. Palpation of the lungs, which should be gentle, also permits detection of nonvisible nodules or abscesses in the parenchyma. Knowing the distribution of a lesion in the lungs also facilitates diagnosis because particular etiologic agents cause lesions with specific distribution. Distribution of lesions is generally described as focal, multifocal, locally extensive, or diffuse. According to their topography, pulmonary lesions can also be classified as cranioventral, dorsocaudal, and so on.

Reports must also contain an estimate of the extent of the pulmonary lesions, preferably expressed as a percentage of the volume of the lungs affected. For instance, a report may read “cranioventral consolidation involving 40% of the lungs.” If the lungs have focal lesions, a rough estimate of the number should also be included in the report. For instance, “numerous (approximately 25), small (1 to 2 cm in diameter), hard nodules were randomly distributed in all lung lobes.”

Two methods are used to examine the nasal structures. The first is making a midsagittal cut through the head and removing the nasal septum; the second is making several transverse sections of the nose at the level of the second premolar teeth. This latter method is preferred when examining pigs suspected of having atrophic rhinitis or animals suspected of having nasal neoplasms.

Histopathology and Biopsies

Microscopic examination of pulmonary tissue is routinely done in diagnostic laboratories. Samples of normal and abnormal lungs, along with other appropriate tissue, should always be submitted in 10% buffered-neutral formalin for histopathologic evaluation. A minimum of four lung samples (left cranial, left caudal, right cranial, and right caudal) should be taken for histopathologic examination in animals with a history of respiratory signs. To improve fixation, a paper towel can be placed over the samples of lung floating in fixative. When detailed evaluation of the alveolar walls is required, lungs can be fixed by a gentle intratracheal injection of fixative; however, this technique displaces transudates and exudates and can artificially cause distention of the perivascular and peribronchial spaces. Lung biopsy specimens are taken only sporadically because complications often outweigh the diagnostic value. However, the use of new techniques, such as endoscopic-directed biopsies, has notably reduced some of these complications. Biopsies of the lungs are recommended in cases of chronic persistent pulmonary disease unresponsive to treatment or intrathoracic masses of undetermined origin. Endoscopic-directed biopsies of the nasal and bronchial mucosa are routinely used in clinical practice and generally have a much better diagnostic value.

Bronchoalveolar Lavage and Tracheal Aspirates

Two valuable diagnostic tools in human medicine, bronchoalveolar lavage (BAL) and tracheal aspirates, have in recent years become more widely used in veterinary clinical diagnosis of respiratory ailments, particularly in horses, dogs, and cats. The basis of BAL is sampling to determine the cellular and biochemical composition of the lung in a respiratory patient live animal by infusing and retrieving sterile fluid via the trachea. BAL is done by inserting a tube directly through the larynx into a bronchus, or transtracheally by inserting a tube through a needle percutaneously into the cervical trachea. Microscopic examination of properly collected, stored, and processed samples may reveal many erythrocytes and siderophages in pulmonary hemorrhage or left-sided heart failure; inclusion bodies or syncytial cells in viral pneumonias; increased number of leukocytes in pulmonary inflammation; abundant mucus in asthma or equine heaves (chronic obstructive pulmonary disease [COPD]); presence of pulmonary pathogens, such as parasites, fungi, and bacteria; or tumor cells in cases of pulmonary neoplasia. In the healthy patient, 80% to 95% of the BAL cells are pulmonary alveolar macrophages (see Fig. 9-10).

Diseases of the Respiratory System

Nasal Cavity and Sinus Mucosa

Pattern of Injury and Host Response

The conducting portion of the respiratory system is lined by pseudostratified columnar ciliated epithelium (most of the nasal cavity, paranasal sinuses, part of the larynx, and all of the trachea and bronchi), olfactory epithelium (part of the nasal cavity, particularly ethmoidal conchae), and squamous epithelium (nasal vestibulum and parts of the larynx). The pattern of injury, inflammation, and host response (wound healing) is characteristic for each of these three types of epithelium and independent of its anatomic location.

Pseudostratified ciliated epithelium, which lines most of the nasal cavity and nasopharynx, part of the larynx, and all of the trachea and bronchi, is exquisitely sensitive to injury. When these cells are irreversibly injured, whether caused by a viral infection, trauma, or inhalation of toxic gases, ciliated cells swell, typically lose their attachment to underlying basement membrane, and rapidly exfoliate (Fig. 9-11). A transient and mild exudate of fluid, plasma proteins, and neutrophils covers the ulcer. In the absence of complications or secondary bacterial infections, a specific type of progenitor cell known as nonciliated secretory cells, which is normally present in the mucosa, migrates to cover the denuded basement membrane and undergoes mitosis, eventually differentiating into new ciliated epithelial cells (see Fig. 9-11). Cellular migration, proliferation, and attachment are regulated by locally released growth factors and extracellular matrix (ECM) proteins such as collagen, integrins, and fibronectin. The capacity of ciliated epithelium to repair itself is remarkably effective. For example, epithelial healing in an uncomplicated ulcer of the tracheal mucosa can be completed in only 10 days. This sequence of cell degeneration, exfoliation, ulceration, mitosis, and repair is typically present in many viral infections in which viruses replicate in nasal, tracheal, and bronchial epithelium, causing extensive mucosal ulceration. Examples of transient infections of this type include human colds (rhinoviruses), infectious bovine rhinotracheitis (bovine herpesvirus 1), feline rhinotracheitis (feline herpesvirus 1), and canine infectious tracheobronchitis (CAV-2 and canine parainfluenza-2).

If damage to the mucociliary blanket becomes chronic, goblet cell hyperplasia takes place, leading to excessive mucus production (hypersecretion) and reduced mucociliary clearance, and when there is loss of basement membrane, repair is by fibrosis and granulation tissue (scarring). In the most severe cases, prolonged injury causes squamous metaplasia, which together with scarring, causes airway obstruction and an impediment to mucociliary clearance. In laboratory rodents, hyperplastic and metaplastic changes, such as those seen in nasal polyps and squamous metaplasia, are considered a prelude to neoplasia.

The second type of epithelium lining the conducting system is the sensory olfactory epithelium, present in parts of the nasal mucosa, notably in the ethmoidal conchae. The patterns of degeneration, exfoliation, and inflammation in the olfactory epithelium are similar to those of the ciliated epithelium, except that olfactory epithelium has only limited capacity for regeneration. When olfactory epithelium has been irreversibly injured, olfactory cells swell, separate from adjacent sustentacular cells, and finally exfoliate into the nasal cavity. Once the underlying basement membrane of the olfactory epithelium is exposed, cytokines are released by leukocytes and endothelial cells, and inflammatory cells move into the affected area. When damage is extensive, ulcerated areas of olfactory mucosa are replaced by ciliated and goblet cells or squamous epithelium, or by fibrous tissue, all of which eventually cause reduction (hyposmia) or loss of olfactory function (anosmia). Repair of the olfactory epithelium is slower and less efficient than repair of the respiratory epithelium. Neurons in the olfactory mucosa have the unique ability to regenerate, a fact that is being explored as a potential source of new neurons in the treatment of spinal cord injury.

Squamous epithelium, located in the vestibular region of the nose (mucocutaneous junctions), is the third type of epithelium present in the nasal passages. Compared with ciliated and olfactory epithelia, nasal squamous epithelium is quite resistant to all forms of injury.

Anomalies of the Nasal Cavity

Localized congenital anomalies of the nasal cavity are rare in domestic animals and are often merely part of a more extensive craniofacial deformity (e.g., cyclops) or a component of generalized malformation (e.g., chondrodysplasia). Congenital anomalies involving the nasal cavity and sinuses, such as choanal atresia (lack of communication between the nasal cavity and pharynx), some types of chondrodysplasia, and osteopetrosis, are incompatible with life. Examples of nonfatal congenital anomalies include cystic nasal conchae, deviation of nasal septum, cleft upper lip (harelip, cheiloschisis), hypoplastic turbinates, and cleft palate (palatoschisis) (Fig. 7-1). Bronchoaspiration and aspiration pneumonia are common sequelae to cleft palate. Nasal and paranasal sinus cysts are slowly growing and expansive lesions that mimic neoplasia and cause severe cranial deformations in horses. These large cysts presumably originate congenitally from dentigerous tissue. As in other organs or systems, it is extremely difficult to determine the actual cause (genetic versus congenital) of anomalies based on pathologic evaluation.

Metabolic Disturbances of the Nasal Cavity

Metabolic disturbances affecting the nasal cavity and sinuses are also rare in domestic animals. Amyloidosis, the deposition of amyloid protein (fibrils with a β-pleated configuration) in various tissues, has been sporadically reported in the nasal cavity of horses and humans. Microscopic lesions are similar to those seen in other organs and consist of a deposition of hyaline amyloid material in nasal mucosa that is confirmed by a histochemical stain, such as Congo red. Unlike amyloidoses in other organs of domestic animals where amyloid is generally of the reactive type (amyloid AA), equine nasal amyloidosis appears to be of the immunocytic type (amyloid AL). Affected horses with large amyloid masses have difficulty breathing because of nasal obstruction, and may exhibit epistaxis and reduced athletic performance; on clinical examination, large, firm nodules resembling neoplasms (amyloidoma) can be observed in the alar folds, rostral nasal septum, and floor of nasal cavity.

Circulatory Disturbances of the Nasal Cavity

Hemorrhage: Epistaxis is the clinical term used to denote blood flow from the nose (nosebleed) regardless of whether the blood originates from the nasal mucosa or from deep in the lungs such as in horses with “exercise-induced pulmonary hemorrhage.” Unlike blood in the digestive tract, where the approximate anatomic location of the bleeding can be estimated by the color the blood imparts to fecal material, blood in the respiratory tract is always red. This fact is due to the rapid transport of blood out of the respiratory tract by the mucociliary blanket and during breathing. Hemorrhages into the nasal cavity can be the result of local trauma, originate from erosions of submucosal vessels by inflammation (e.g., guttural pouch mycosis), or be caused by neoplasms. Hemoptysis refers to the presence of blood in sputum or saliva (coughing or spitting blood) and is most commonly the result of pneumonia, lung abscesses, ulcerative bronchitis, pulmonary thromboembolisms, and pulmonary neoplasia.

Ethmoidal (progressive) hematomas are important in older horses and are characterized clinically by chronic, progressive, often unilateral nasal bleeding. Grossly or endoscopically, an ethmoidal hematoma appears as a single, soft, tumorlike, pedunculated, expansive, dark red mass arising from the mucosa of the ethmoidal conchae (Fig. 9-12). Microscopic examination reveals a capsule lined by epithelium and hemorrhagic stromal tissue infiltrated with abundant macrophages, some of which are siderophages.

Inflammation of the Nasal Cavity

Inflammation of the nasal mucosa is called rhinitis, and inflammation of the sinuses is called sinusitis. These conditions usually occur together, although mild sinusitis can be undetected. Clinically, rhinosinusitis is characterized by nasal discharge.

The occurrence of infectious rhinitis presupposes an upset in the balance of the normal microbial flora of the nasal cavity. Innocuous bacteria present normally and protect the host through a process called competitive exclusion, whereby potential pathogens are kept at a harmless level. Disruption of this protective mechanism can be caused by respiratory viruses, pathogenic bacteria, fungi, irritant gases, environmental changes, immunosuppression, local trauma, stress, or prolonged antibacterial therapy.

Inflammatory processes in the nasal cavity are not life threatening and usually resolve completely. However, some adverse sequelae in cases of infectious rhinitis include bronchoaspiration of exudate leading to bronchopneumonia. Chronic rhinitis often leads to destruction of the nasal conchae (turbinates), deviation of the septum, and eventually, craniofacial deformation. Also, nasal inflammation may extend into the sinuses causing sinusitis; into facial bones causing osteomyelitis; through the cribriform plate causing meningitis; into the Eustachian tubes causing otitis media; and even into the inner ear causing otitis interna and vestibular syndrome (abnormal head tilt and abnormal gait), which in severe cases may lead to emaciation.

Based on the nature of exudate, rhinitis can be classified as serous, fibrinous, catarrhal, purulent, or granulomatous. These types of inflammatory reactions can progress from one to another in the course of the disease (i.e., serous to catarrhal to purulent), or in some instances exudates can be mixed, such as those seen in mucopurulent, fibrinohemorrhagic, or pyogranulomatous rhinitis. Microscopic examination of impression smears or nasal biopsy, and bacterial or fungal cultures are generally required in establishing the cause of inflammation. Common sequels to rhinitis are hemorrhage, ulcers, and in some cases polyps (hyperplasia) arising from inflamed nasal mucosa. Rhinitis also can be classified according to the age of the lesions as acute, subacute, or chronic; to the severity of the insult as mild, moderate, or severe; and to the etiologic agent as viral, allergic, bacterial, mycotic, parasitic, traumatic, or toxic.

Purulent (Suppurative) Rhinitis: Purulent (suppurative) rhinitis is characterized by a neutrophilic exudate, which occurs when the nasal mucosa suffers a more severe injury that generally is accompanied by mucosal necrosis and secondary bacterial infection. Cytokines, leukotrienes, complement activation, and bacterial products cause exudation of leukocytes, especially neutrophils, which mix with nasal secretions, including mucus. Grossly, the exudate in suppurative rhinitis is thick and opaque, but it can vary from white to green to brown, depending on the types of bacteria and type of leukocytes (neutrophils or eosinophils) present in the exudate (Fig. 9-13 and Web Fig. 9-3). In severe cases, the nasal passages are completely blocked by the exudate. Microscopically, neutrophils can be seen in the submucosa and mucosa and form plaques of exudate on the mucosal surface. Neutrophils are commonly found marginated in vessels, in the lamina propria, and in between epithelial cells in their migration to the surface of the mucosa.

Fibrinous Rhinitis: Fibrinous rhinitis is a reaction that occurs when nasal injury causes a severe increase in vascular permeability, resulting in abundant exudation of plasma fibrinogen, which coagulates into fibrin. Grossly, fibrin appears like a yellow, tan, or gray rubbery mat on nasal mucosa. Fibrin accumulates on the surface and forms a distinct film of exudate sometimes referred to as pseudomembrane (Fig. 9-14). If this fibrinous exudate can be removed, leaving an intact underlying mucosa, it is termed a croupous or pseudodiphtheritic rhinitis. Conversely, if the pseudomembrane is difficult to remove and leaves an ulcerated mucosa, it is referred to as diphtheritic or fibrinonecrotic rhinitis. The term diphtheritic was derived from human diphtheria, which causes a severe and destructive inflammatory process of the nasal, tonsillar, pharyngeal, and laryngeal mucosa. Microscopically, the lesions include a perivascular edema with fibrin, a few neutrophils infiltrating the mucosa, and superficial plaques of exudate consisting of fibrin strands mixed with leukocytes and cellular debris covering a necrotic and ulcerated epithelium. Fungal infections, such as aspergillosis, can cause a severe fibrinonecrotizing rhinitis.

Granulomatous Rhinitis: Granulomatous rhinitis is a reaction in the nasal mucosa and submucosa that is characterized by infiltration of numerous activated macrophages mixed with a few lymphocytes and plasma cells. In some cases, inflammation leads to the formation of polypoid nodules that in severe cases are large enough to cause obstruction of the nasal passages (Fig. 9-15). Granulomatous rhinitis is generally associated with chronic allergic inflammation or infection with specific organisms, such as those of the systemic mycoses (see the section on Lungs), tuberculosis, or rhinosporidiosis, and with foreign bodies. In some cases, the cause of granulomatous rhinitis cannot be determined.

Sinusitis: Sinusitis occurs sporadically in domestic animals and is frequently combined with rhinitis (rhinosinusitis), or it occurs as a sequela to penetrating or septic wounds of the nasal, frontal, maxillary, or palatine bones; improper dehorning in young cattle, which exposes the frontal sinus; or maxillary tooth infection in horses and dogs (maxillary sinus). Based on the type of exudate, sinusitis is classified as serous, catarrhal, fibrinous (rare), purulent, or granulomatous. Paranasal sinuses have poor drainage; therefore exudate tends to accumulate, causing mucocele (accumulation of mucus) or empyema (accumulation of pus) (Fig. 9-16). Chronic sinusitis may extend into the adjacent bone (osteomyelitis) or through the ethmoidal conchae into the meninges and brain (meningitis and encephalitis).

Specific Diseases of the Nasal Cavity and Sinuses

Equine Nasal Diseases:

Equine Viral Infections: Viruses, such as equine viral rhinopneumonitis virus, influenza virus, adenovirus, and rhinovirus, cause mild and generally transient respiratory infections in horses. The route of infection for these respiratory viruses is typically aerogenous. All these infections are indistinguishable clinically; signs consist mainly of malaise, fever, coughing, and nasal discharge varying from serous to purulent. Viral respiratory infections are common medical problems in adult horses.

Equine viral rhinopneumonitis: Equine viral rhinopneumonitis (EVR) is caused by two ubiquitous equine herpesviruses (EHV-1 and EHV-4) and may be manifested as a mild respiratory disease in weanling foals and young racehorses, as a neurologic disease (myeloencephalopathy), or as abortion in mares. The portal of entry for the respiratory form is typically aerogenous, and the disease is generally transient; thus the primary viral-induced lesions in the nasal mucosa and lungs are rarely seen at necropsy unless complicated by secondary bacterial rhinitis, pharyngitis, or bronchopneumonia. Studies with polymerase chain reaction (PCR) techniques have demonstrated that, like other herpesvirus, EHV-1 and EHV-4 persist latently in the trigeminal ganglia for long periods of time. Reactivation because of stress or immunosuppression and subsequent shedding of the virus are the typical source of infection for susceptible animals on the farm.

Equine influenza: Equine influenza is a common, highly contagious, and self-limiting upper respiratory infection of horses caused by aerogenous exposure to type A strains of influenza virus (H7N7 [A/equi-1] and H3N8 [A/equi-2]). Equine influenza has high morbidity (outbreaks) but low mortality, and it is clinically characterized by fever, conjunctivitis, and serous nasal discharge. It occurs mainly in 2- to 3-year-old horses at the racetrack. As with human influenza, equine influenza is usually a mild disease, but occasionally it can cause severe bronchointerstitial pneumonia with pulmonary edema. In some horses, impaired defense mechanisms caused by the viral infection are complicated by a secondary bacterial bronchopneumonia caused by opportunistic organisms (Streptococcus zooepidemicus, Staphylococcus aureus, or Bacteroides sp.) found in the normal flora of the upper respiratory tract. Uncomplicated cases of equine influenza are rarely seen in the postmortem room.

Equine Bacterial Infections: Strangles, Glanders, and Melioidosis: Strangles, glanders, and melioidosis of horses are all systemic bacterial diseases that cause purulent rhinitis and suppuration in various organs. These diseases are grouped as upper respiratory diseases because nasal discharge is often the most notable clinical sign.

Strangles: Strangles is an infectious and highly contagious disease of Equidae that is caused by Streptococcus equi ssp. equi (Streptococcus equi). It is characterized by suppurative rhinitis and lymphadenitis (mandibular and retropharyngeal lymph nodes) with occasional hematogenous dissemination to internal organs. Unlike Streptococcus equi ssp. zooepidemicus (Streptococcus zooepidemicus) and Streptococcus dysgalactiae ssp. equisimilis (Streptococcus equisimilis), Streptococcus equi is not part of the normal nasal flora. Infection occurs when susceptible horses come into contact with feed, exudate, or air droplets containing the bacterium. After penetrating through the nasopharyngeal mucosa, Streptococcus equi drains to the regional lymph nodes—mandibular and retropharyngeal lymph nodes—via lymphatic vessels. The gross lesions in horses with strangles (mucopurulent rhinitis) correlate with clinical findings and consist of copious amounts of mucopurulent exudate in the nasal passages with notable hyperemia of nasal mucosa. Affected lymph nodes are enlarged and may contain abscesses filled with thick purulent exudate (purulent lymphadenitis). The term bastard strangles is used in cases in which hematogenous dissemination of Streptococcus equi results in metastatic abscesses in such organs as the lungs, liver, spleen, kidneys, or brain or in the joints. This form of strangles is often fatal.

Common sequelae to strangles include bronchopneumonia caused by aspiration of nasopharyngeal exudate; laryngeal hemiplegia (“roaring”), resulting from compression of the recurrent laryngeal nerves by enlarged retropharyngeal lymph nodes; facial paralysis and Horner syndrome caused by compression of sympathetic nerves that run dorsal to the medial retropharyngeal lymph node; and purpura hemorrhagica as a result of vasculitis caused by deposition of Streptococcus equi antigen-antibody complexes in arterioles, venules, and capillaries of the skin and mucosal membranes. In severe cases, nasal infection extends directly into the paranasal sinuses or to the guttural pouches via the Eustachian tubes, causing inflammation and accumulation of pus (guttural pouch empyema). Rupture of abscesses in the mandibular and retropharyngeal lymph nodes leads to suppurative inflammation of adjacent subcutaneous tissue (cellulitis), and in severe cases the exudate escapes through cutaneous fistulas.

Strangles can affect horses of all ages, but it is most commonly seen in foals and young horses. It is clinically characterized by cough, nasal discharge, conjunctivitis, and painful swelling of regional lymph nodes. Some horses become carriers and a source of infection to other horses.

Sep 17, 2016 | Posted by in GENERAL | Comments Off on Respiratory System, Mediastinum, and Pleurae
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