Respiratory System, Mediastinum, and Pleurae

Congestion and Hyperemia: The nasal mucosa is well vascularized and is capable of rather dramatic variation in blood flow, whether passively as a result of interference with venous return (congestion) or actively because of vasodilation (hyperemia). Congestion of the mucosal vessels is a nonspecific lesion commonly found at necropsy and presumably associated with the circulatory failure preceding death (e.g., heart failure, bloat in ruminants in which the increased intraabdominal pressure causes increased intrathoracic pressure impeding the venous return from the head and neck). Hyperemia of the nasal mucosa is seen in early stages of inflammation, whether caused by irritations (e.g., ammonia, regurgitated feed), viral infections, secondary bacterial infections, allergy, or trauma.

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.

Serous Rhinitis: Serous rhinitis is the mildest form of inflammation and is characterized by hyperemia and increased production of a clear fluid locally manufactured by serous glands present in the nasal submucosa. Serous rhinitis is of clinical interest only. It is caused by mild irritants or cold air, and it occurs during the early stages of viral infections, such as the common cold in humans, upper respiratory tract infections in animals, or in mild allergic reactions.

Catarrhal Rhinitis: Catarrhal rhinitis is a slightly more severe process and has, in addition to serous secretions, a substantial increase in mucus production by increased activity of goblet cells and mucous glands. A mucous exudate is a thick, translucent, or slightly turbid viscous fluid, sometimes containing a few exfoliated cells, leukocytes, and cellular debris. In chronic cases, catarrhal rhinitis is characterized microscopically by notable hyperplasia of goblet cells. As the inflammation becomes more severe, the mucus is infiltrated with neutrophils giving the exudate a cloudy mucopurulent appearance. This exudate is referred to as mucopurulent.

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).

Equine Nasal Diseases:

Bovine Nasal Diseases:

Ovine and Caprine Nasal Disease: Oestrus ovis (Diptera: Oestridae; nasal bot) is a brownish fly about the size of a honeybee that deposits its first-stage larvae in the nostrils of sheep in most parts of the world. Microscopic larvae mature into large bots (maggots), which spend most of their larval stages in nasal passages and sinuses, causing irritation, inflammation, and obstruction of airways. Matured larvae drop to the ground and pupate into flies. This type of parasitism in which living tissues are invaded by larvae of flies is known as myiasis (Fig. 9-19). Although Oestrus ovis is a nasal myiasis primarily of sheep, it sporadically affects goats, dogs, and sometimes humans (shepherds). The presence of the larvae in nasal passages and sinuses causes chronic irritation and erosive mucopurulent rhinitis and sinusitis; bots of Oestrus ovis can be found easily if the head is cut to expose the nasal passages and paranasal sinuses. Rarely, larvae of Oestrus ovis penetrate the cranial vault through the ethmoidal plate, causing direct or secondary bacterial meningitis.

Infectious rhinitis is only sporadically reported in goats, and most of these cases are caused by Pasteurella multocida or Mannheimia haemolytica. The lesions range from a mild serous to catarrhal or mucopurulent inflammation.

Porcine Nasal Diseases:

Canine Nasal Diseases: Dogs have no specific viral infections affecting exclusively the nasal cavity or sinuses. Acute rhinitis occurs as part of general respiratory disease caused by several distinct viruses, such as canine distemper virus, CAV-1 and -2, canine parainfluenza virus, reovirus, and canine herpesvirus. The viral lesions in the respiratory tract are generally transient, but the effect of the virus on other tissues and cells can be fatal, as in distemper encephalitis in dogs. As in other species, secondary bacterial rhinitis, sinusitis, and pneumonia are possible sequelae of respiratory viral infections; Bordetella bronchiseptica, Escherichia coli, and Pasteurella multocida are the most common isolates in dogs with bacterial rhinitis. A nonspecific (idiopathic) chronic lymphoplasmatic rhinitis is occasionally seen in dogs. Immotile cilia syndrome (ciliary dyskinesia), a congenital disease, reduces mucociliary clearance and is an important factor in recurrent canine rhinosinusitis, bronchitis, bronchiectasis, and pneumonia.

Feline Nasal Diseases:

Endemic Ethmoidal Tumors: A unique group of nasal carcinomas (enzootic nasal tumors, enzootic intranasal tumors, and enzootic nasal carcinoma) of sheep, goats, and cattle arise from the surface epithelium and glands of the ethmoidal conchae. These types of carcinomas are caused by an oncogenic retrovirus, and the neoplasm has been successfully transmitted to susceptible animals by inoculation of virus or infected tissues. Endemic ethmoidal tumors are typically invasive but do not metastasize (Fig. 9-24). In some regions of the world, ethmoid tumors have been reported in horses and pigs, particularly in those farms where the endemic nasal tumors of ruminants are known to occur.

Nasal Polyps and Nasal Cysts Resembling Neoplasms: Nonneoplastic exophytic masses that resemble neoplasms are commonly found in horses, cats, and to a lesser extent other species. In horses, polyps tend to form in the ethmoidal region, whereas in cats, polyps are most frequently found in the nasopharynx and Eustachian tubes. The pathogenesis of these benign growths is uncertain, although in many cases they follow chronic rhinitis or sinusitis. Grossly, polyps appear as firm, pedunculated nodules of various sizes protruding from the nasal mucosa into the nasal passages; the surface may be smooth, ulcerated, secondarily infected, and hemorrhagic. Microscopically, polyps are characterized by a core of well-vascularized stromal tissue that contains inflammatory cells and are covered by pseudostratified or squamous epithelium.

Nasal and paranasal sinus cysts are common in horses and are medically important because they clinically mimic neoplasms or infections. Although not considered a neoplastic growth, cysts are expansive and cause deformation or destruction of the surrounding bone. These cysts are typically composed of an epithelial cell capsule filled with yellow or hemorrhagic fluid and do not recur after surgical removal. Ethmoidal hematomas also resemble nasal tumors in horses.

Brachycephalic Airway Syndrome: Brachycephalic airway syndrome is a clinical term that refers to increased air-flow resistance caused by stenotic nostrils and nasal meatuses and an excessively long soft palate. These abnormalities are present in brachycephalic canine breeds such as bulldogs, boxers, Boston terriers, pugs, Pekingese, and others. The defects are a result of a mismatch of the ratio of soft tissue to cranial bone and the obstruction of airflow by excessive length of the palatine soft tissue. Secondary changes, such as nasal and laryngeal edema caused by forceful inspiration, eventually lead to severe upper airway obstruction, respiratory distress, and exercise intolerance.

Hypoplastic Epiglottis, Epiglottic Entrapment, and Dorsal Displacement of the Soft Palate: Anomalies, such as hypoplastic epiglottis, epiglottic entrapment, and dorsal displacement of the soft palate, are important causes of respiratory problems and reduced athletic performance in horses. An undersized epiglottis is prone to being entrapped below the arytenoepiglottic fold, causing an equine syndrome known as epiglottic entrapment. This syndrome also occurs in horses with lateral deviation and deformity of epiglottis, epiglottic cysts, or necrosis of the tip of the epiglottis. Hypoplastic epiglottis also occurs in pigs. Dorsal displacement of the soft palate, particularly during exercise, narrows the lumen of the nasopharynx and creates abnormal air turbulence in the conducting system of horses. Epiglottic entrapment is clinically characterized by airway obstruction, exercise intolerance, respiratory noise, and cough.

Subepiglottic and Pharyngeal Cysts: Anomalous lesions, such as subepiglottic and pharyngeal cysts, are occasionally seen in horses, particularly in Standardbred and Thoroughbred race horses. These cysts vary in size (1 to 9 cm) and occur most commonly in the subepiglottic area and to a lesser extent in the dorsal pharynx, larynx, and soft palate. Cysts are lined by squamous or pseudostratified epithelium and contain thick mucus. Large cysts cause airway obstruction, reduced exercise tolerance, or dysphagia and predispose to bronchoaspiration of food.

Tracheal Agenesis and Tracheal Hypoplasia: Tracheal hypoplasia occurs most often in English bulldogs and Boston terriers; the tracheal lumen is decreased in diameter throughout its length.

Tracheal Collapse and Tracheal Stenosis: Tracheal collapse with reduction in tracheal patency occurs in toy, miniature, and brachycephalic breeds of dogs, in which the condition is also called tracheobronchial collapse or central airway collapse. The defect also occurs in horses, cattle, and goats. By radiographic, endoscopic, or gross examination, there is dorsoventral flattening of the trachea with concomitant widening of the dorsal tracheal membrane, which may then prolapse ventrally into the lumen (Fig. 9-25). Most commonly, the defect extends the entire length of the trachea and only rarely affects the cervical portion alone. Affected segments with a reduced lumen contain froth and even are covered by a diphtheritic membrane. In horses, the so-called scabbard trachea is characterized by lateral flattening, so that the tracheal lumen is reduced to a narrow vertical slit.

Segmental tracheal collapse causing stenosis has been associated with congenital and acquired abnormalities. In severe cases, abnormal cartilaginous glycoproteins and loss of elasticity of tracheal rings causes the trachea to collapse. In some other cases, it is an acquired tracheal lesion that follows trauma, compression caused by extraluminal masses, peritracheal inflammation, and flawed tracheotomy or transtracheal aspirate techniques.

Other tracheal anomalies include tracheoesophageal fistula, which is most commonly found in humans and sporadically in dogs and cattle. Congenital fistulas can occur at any site of the cervical or thoracic segments of the trachea. Acquired tracheoesophageal fistula can be a complication of improper intubation, tracheotomy, or esophageal foreign body.

Laryngeal Hemiplegia: Laryngeal hemiplegia (paralysis), sometimes called roaring in horses, is a common but obscure disease characterized by atrophy of the dorsal and lateral cricoarytenoid muscles (abductor and adductor of the arytenoid cartilage), particularly on the left side. Muscular atrophy is most commonly caused by a primary denervation (recurrent laryngeal neuropathy) of unknown cause (idiopathic axonopathy) and to a much lesser extent, secondary nerve damage (see the section on Denervation Atrophy in Chapters 14 and 15). Idiopathic laryngeal hemiplegia is an incurable axonal disease (axonopathy) of the cranial laryngeal nerve that affects mostly larger horses. Secondary laryngeal hemiplegia is rare and occurs after nerve damage caused by other pathologic processes such as compression or inflammation of the left recurrent laryngeal nerve. The medial retropharyngeal lymph nodes are located immediately ventral to the floor of the guttural pouches. As a result of this close anatomic relationship, swelling or inflammation of the guttural pouches and retropharyngeal lymph nodes often results in secondary damage to the laryngeal nerve. Common causes of secondary nerve damage (Wallerian degeneration) include guttural pouch mycosis, retropharyngeal abscesses, inflammation because of iatrogenic injection into the nerves, neck injury, and metastatic neoplasms involving the retropharyngeal lymph nodes (e.g., lymphosarcoma).

Grossly, the affected laryngeal muscle in a horse with laryngeal hemiplegia is pale and smaller than normal (muscle atrophy) (Fig. 9-26). Microscopically, muscle fibers have lesions of denervation atrophy (see Chapters 14 and 15). Atrophy of laryngeal muscles also occurs in dogs as an inherited condition (Siberian husky and Bouvier des Flandres), as a degenerative neuropathy in older dogs, secondary to laryngeal trauma in all species (e.g., choke chain damage), or to hepatic encephalopathy in horses.

The abnormal inspiratory sounds (roaring) during exercise in horses with laryngeal hemiplegia are caused by paralysis of the left dorsal and lateral cricoarytenoid muscles, which cause incomplete dilation of the larynx, obstructing of airflow, and vibration of vocal cords.

Laryngeal and Tracheal Hemorrhages: Hemorrhages in these sites occur as mucosal petechiae and are most commonly seen in coagulopathies; inflammation; septicemia and sepsis, particularly in pigs with classical swine fever (hog cholera); African swine fever or salmonellosis; and horses with equine infectious anemia. Severe dyspnea and asphyxia before death can cause congestion, ecchymosis, and petechiae in the laryngeal and tracheal mucosa; this lesion must be differentiated from postmortem imbibition of hemoglobin in autolyzed carcasses (see Chapter 1).

Laryngeal Edema: Laryngeal edema is a common feature of acute inflammation, but it is particularly important because swelling of the epiglottis and vocal cords can obstruct the laryngeal orifice, resulting in asphyxiation. Laryngeal edema occurs in pigs with edema disease; in horses with purpura hemorrhagica; in cattle with acute interstitial pneumonia; in cats with systemic anaphylaxis; and in all species as a result of trauma, improper endotracheal tubing, inhalation of irritant gases (e.g., smoke), local inflammation, and allergic reactions. Grossly the mucosa of the epiglottis and vocal cords is thickened and swollen, often protrudes dorsally onto the epiglottic orifice, and has a gelatinous appearance (Fig. 9-27).

Tracheal Edema and Hemorrhage: Tracheal edema and hemorrhage syndrome of feeder cattle, also known as the honker syndrome or tracheal stenosis of feedlot cattle, is a poorly documented acute disease of unknown cause, most often seen during the summer months. Severe edema and a few hemorrhages are present in the mucosa and submucosa of the dorsal surface of the trachea, extending caudally from the midcervical area as far as the tracheal bifurcation. On a cut section, the tracheal mucosa is diffusely thickened and gelatinous. Clinical signs include inspiratory dyspnea that can progress to oral breathing, recumbency, and death by asphyxiation in less than 24 hours.

Pharyngitis, Laryngitis, and Tracheitis: Inflammation of the pharynx, larynx, and trachea are important because of their potential to obstruct airflow and to lead to aspiration pneumonia. The pharynx is commonly affected by infectious diseases of the upper respiratory and upper digestive tracts, and the trachea can be involved by extension from both the lungs and larynx.

Intraluminal foreign bodies in the pharynx, such as medicament boluses, apples, or potatoes, can move down and obstruct the larynx and trachea. Also, pharyngeal obstruction can be caused by masses in surrounding tissue such as neoplasms of the thyroid gland, thymus, and parathyroid glands.

Pharyngeal Perforation: A number of nonspecific insults can cause lesions and clinical signs. Trauma may take the form of penetrating wounds in any species: perforation of the caudodorsal wall of the pharynx from the improper use of drenching or balling guns in sheep, cattle, and pigs; choking injury because of the use of collars in dogs and cats; and the shearing forces of bite wounds. The results of the trauma may be minimal (local edema and inflammation) or as serious as complete luminal obstruction by exudate. Foreign bodies may be lodged anywhere in the pharyngeal region; the location and size determine the occurrence of dysphagia, regurgitation, dyspnea, or asphyxiation. Pigs have a unique structure known as the pharyngeal diverticulum (4 cm long in adult pigs), which is located in the pharyngeal wall rostral and dorsal to the esophageal entrance. It is important because barley awns may lodge in the diverticulum, causing an inflammatory swelling that affects swallowing. The diverticular wall may be perforated by awns or drenching syringes, which results in an exudate that can extend down the tissue planes between muscles of the neck and even into the mediastinum. The pharynx of the dog may also be damaged by trauma from chicken bones, sticks, and needles, resulting in the formation of a pharyngeal abscess.

Equine Pharyngeal Lymphoid Hyperplasia: Equine pharyngeal lymphoid hyperplasia, or pharyngitis with lymphoid follicular hyperplasia, is a common cause of partial upper airway obstruction in horses, particularly in 2- and 3-year-old racehorses. Lymphoid hyperplasia is also seen in healthy horses as part of a response to mild chronic pharyngitis, which in many instances tends to regress with age in older animals. The cause is undetermined, but chronic bacterial infection combined with environmental factors may cause excessive antigenic stimulation and lymphoid hyperplasia. The gross lesions, visible endoscopically or at necropsy, consist of variably sized (1 to 5 mm) white foci located on the dorsolateral walls of the pharynx and extend into the openings of the guttural pouches and onto the soft palate. In severe cases, lesions may appear as pharyngeal polyps. Microscopically, the lesions consist of large aggregates of lymphocytes and plasma cells in the pharyngeal mucosa. Clinical signs consist of stertorous inspiration, expiration, or both.

Inflammation of Guttural Pouches: The guttural pouches of horses are large diverticula (300 to 500 mL) of the ventral portion of the auditory (eustachian) tubes. These diverticula are therefore exposed to the same pathogens as the pharynx and have drainage problems similar to the pathogens of sinuses. Although it is probable that various pathogens, including viruses, can infect them, the most common pathogens are fungi, which cause guttural pouch mycosis and guttural pouch empyema in the horse. Because of the close anatomic proximity of guttural pouches to the internal carotid arteries, cranial nerves (VII, IX, X, XI, and XII), and atlantooccipital joint, disease of these diverticula may involve these structures and cause a variety of clinical signs in horses.

Guttural pouch mycosis occurs primarily in stabled horses and is caused by Aspergillus fumigatus and other Aspergillus sp. Infection is usually unilateral and presumably starts with the inhalation of spores from moldy hay. Grossly, the mucosal surfaces of the dorsal and lateral walls of the guttural pouch mucosa are first covered by focal, rounded, raised plaques of diphtheritic (fibrinonecrotic) exudate, which with time can become confluent and grow into a large fibrinonecrotic mass (Fig. 9-28). Microscopically, the lesions are severe necrotic inflammation of the mucosa and submucosa with widespread vasculitis and intralesional fungal hyphae. Necrosis of the wall of the guttural pouches can extend into the wall of the adjacent internal carotid artery causing hemorrhage into the lumen of the guttural pouch and recurrent epistaxis. Invasion of the internal carotid artery causes arteritis, which can also lead to formation of an aneurysm and fatal bleeding into the guttural pouches. In other cases, the fungi may be angioinvasive, leading to the release of mycotic emboli into the internal carotid artery, generally resulting in multiple cerebral infarcts. Dysphagia, another clinical sign seen in guttural pouch mycosis, is associated with damage to the pharyngeal branches of the vagus and glossopharyngeal nerves, which lie on the ventral aspect of the pouches. Horner’s syndrome results from damage to the cranial cervical ganglion and sympathetic fibers located in the caudodorsal aspect of the pouches. Finally, equine laryngeal paralysis (hemiplegia) can result from damage to the laryngeal nerves as previously described in the section on Laryngeal Hemiplegia.

Empyema of guttural pouches is a sequela to suppurative inflammation of the nasal cavities, most commonly from Streptococcus equi infection (strangles). In severe cases, the entire guttural pouch can be filled with purulent exudate (Fig. 9-29). The sequelae are similar to those of guttural pouch mycosis except that there is no erosion of the internal carotid artery. It is clinically characterized by nasal discharge, enlarged retropharyngeal lymph nodes, painful swelling of the parotid region, dysphagia, and respiratory distress.

Guttural pouch tympany develops sporadically in young horses when excessive air accumulates in the pouch from the one-way valve effect caused by inflammation or malformation of the Eustachian tube. It is generally unilateral and characterized by nonpainful swelling of the parotid region.

Necrotic Laryngitis: Necrotic laryngitis (calf diphtheria, laryngeal necrobacillosis) is a common disease of feedlot cattle and cattle affected with other diseases, with nutritional deficiencies, or housed under unsanitary conditions. It also occurs sporadically in sheep and pigs. Necrotic laryngitis, caused by Fusobacterium necrophorum, is part of the syndrome termed laryngeal necrobacillosis, which can include lesions of the tongue, cheeks, palate, and pharynx. An opportunistic pathogen, Fusobacterium necrophorum produces several exotoxins and endotoxins after gaining entry either through lesions of viral infections, such as IBR and vesicular stomatitis in cattle, or after traumatic injury produced by feed or careless use of specula or balling guns.

The gross lesions, regardless of location in the mouth or larynx (most common in the mucosa overlying the laryngeal cartilages), consist of well-demarcated, dry, yellow-gray, thick-crusted, and fibrinonecrotic exudate (Fig. 9-30) that in the early stages is bounded by a zone of active hyperemia. Deep ulceration develops, and if the lesion does not result in death, healing is by granulation tissue formation. Microscopically, the necrotic foci are first surrounded by hyperemic borders, then by a band of leukocytes, and finally the ulcers heal by granulation tissue and collagen (fibrosis). The lesions can extend deep into the submucosal tissue. Numerous bacteria are evident at the advancing edge.

There are numerous and important sequelae to calf diphtheria; the most serious is death from severe toxemia or overwhelming fusobacteremia. Sometimes, the exudate may be copious enough to cause laryngeal obstruction and asphyxiation or be aspirated and cause bronchopneumonia. The clinical signs of necrotic laryngitis are fever, anorexia, depression, halitosis, moist painful cough, dysphagia, and inspiratory dyspnea and ventilatory failure because of fatigue of the respiratory muscles (diaphragm and intercostal).

Laryngeal Contact Ulcers: Ulcerative lesions in the larynx are commonly found in feedlot cattle. Grossly, the laryngeal mucosa reveals circular ulcers (up to 1 cm in diameter), which may be unilateral or bilateral and sometimes deep enough to expose the underlying arytenoid cartilages. The cause has not been established, but causal agents, such as viral, bacterial, and traumatic, have been proposed, along with increased frequency and rate of closure of the larynx (excessive swallowing and vocalization) when cattle are exposed to market and feedlot stresses such as dust, pathogens, and interruption of feeding. Contact ulcers predispose a calf to diphtheria (Fusobacterium necrophorum) and laryngeal papillomas. Ulceration of the mucosa and necrosis of the laryngeal cartilages have also been described in calves, sheep, and horses under the term laryngeal chondritis. Laryngeal abscesses involving the mucosa and underlying cartilage occur as a herd or flock problem in calves and sheep, presumably caused by a secondary infection with Arcanobacterium pyogenes (Actinomyces pyogenes; Corynebacterium pyogenes).

Tracheitis: The types of injury and host inflammatory responses in the trachea are essentially the same as those described for the nasal mucosa. Although tracheal mucosa is prone to aerogenous injury and necrosis, it has a remarkable capacity for repair. The most common causes of tracheitis are viral infections, such as those causing IBR (see Fig. 9-18), EVR, canine distemper, and feline rhinotracheitis. Viral lesions are generally mild and transient but often become complicated with secondary bacterial infections. At the early stages, the mucosa is notably hyperemic and can show white foci of necrosis. In the most severe cases, the affected mucosa detaches from the underlying basement membrane, causing extensive tracheal ulceration.

Chemical tracheitis is also commonly seen after aspiration (Fig. 9-31). Also, inhalation of fumes during barn fires can cause extensive injury and necrosis of the tracheal mucosa. In forensic cases, the presence of carbon pigment in the mucosal surface of trachea, bronchi, and bronchioles indicates that the burned animal was alive during the fire.

According to the exudate, tracheitis in all animal species is classified as fibrinous, catarrhal, purulent, or granulomatous. Chronic polypoid tracheitis occurs in dogs and cats, probably secondary to chronic infection.

Besnoitiosis (Besnoitia Bennetti; Besnoitia Besnoiti): Besnoitiosis (Besnoitia bennetti; Besnoitia besnoiti) is caused by an apicomplexan coccidian parasite, whose life cycle is still unknown. This parasite can cause pedunculated lesions on the skin, sclera, mucosa of the nasal cavity, and larynx of horses and donkeys, cattle, and wild animals. Besnoitiosis has been reported from Africa, Central and South America, and Britain. Grossly, pale, round, exophytic nodules up to 2 cm in diameter can be observed protruding from mucosal surfaces. These nodules microscopically consist of fingerlike projections covered by hyperplastic and sometimes ulcerated epithelium containing numerous thick-walled parasitic cysts with little inflammatory response.

Mammomonogamus (Syngamus) Laryngeus: Mammomonogamus (Syngamus) laryngeus) is a nematode that is seen attached to the laryngeal mucosa of cattle in tropical Asia and South America, and cats (gapeworm) in the Caribbean and southern United States (US). Occasionally, humans with a persistent cough or asthma-like symptoms have the parasite in the larynx or bronchi.

Oslerus (Filaroides) Osleri: Oslerus (Filaroides) osleri is a nematode parasite of dogs and other Canidae that causes characteristic protruding nodules into the lumen at the tracheal bifurcation. They are readily seen on endoscopic examination or at necropsy. In severe cases, these nodules can extend 5 cm cranially or caudally from the tracheal bifurcation and even into primary and secondary bronchi. The disease occurs worldwide, and Oslerus osleri is considered the most common respiratory nematode of dogs.

The gross lesions are variably sized, up to 1 cm, submucosal nodules that extend up to 1 cm into the tracheal lumen (Web Fig. 9-8). Microscopically, a mild mononuclear cell reaction is present when parasites are alive, but with the death of the parasite, an intense foreign body reaction develops with neutrophils and giant cells. Clinically, it can be asymptomatic, although it most often causes a chronic cough that can be exacerbated by exercise or excitement. Severe infestations can result in dyspnea, exercise intolerance, cyanosis, emaciation, and even death in young dogs.

Neoplasms of the Guttural Pouches: Neoplasms of the guttural pouches occur rarely in horses and are usually squamous cell carcinomas.

Neoplasms of the Larynx and Trachea: Laryngeal neoplasms are rare in dogs and extremely so in other species, although they have been reported in cats and horses.

The most common laryngeal neoplasms in dogs are papillomas and squamous cell carcinomas. Other less common tumors are laryngeal rhabdomyoma, previously referred to as laryngeal oncocytoma, and chondromas and osteochondromas. Lymphoma involving the laryngeal tissue is sporadically seen in cats.

When large enough to be obstructive, neoplasms may cause a change or loss of voice, cough, or respiratory distress with cyanosis, collapse, and syncope. Other signs include dysphagia, anorexia, and exercise intolerance. The neoplasm is sometimes visible from the oral cavity and causes swelling of the neck. The prognosis is poor, as most lesions recur after excision.

Tracheal neoplasms are even more uncommon than those of the larynx. The tracheal cartilage or mucosa can be the site of an osteochondroma, leiomyoma, osteosarcoma, mast cell tumor, and carcinoma. Lymphosarcomas in cats can extend from the mediastinum to involve the trachea.

Pulmonary Calcification (“Calcinosis”): Calcification of the lungs occurs in some hypercalcemic states, generally secondary to hypervitaminosis D or from ingestion of toxic (hypercalcemic) plants, such as Solanum malacoxylon (Manchester wasting disease) that contain vitamin D analogs. It is also a common sequela to uremia and hyperadrenocorticism in dogs and to pulmonary necrosis (dystrophic calcification) in most species. Calcified lungs may fail to collapse when the thoracic cavity is opened and have a characteristic “gritty” texture (Fig. 9-33). Microscopically, lesions vary from calcification of the alveolar basement membranes (see Fig. 9-33) to heterotopic ossification of the lungs. In most cases, pulmonary calcification in itself has little clinical significance, although its cause (e.g., uremia or vitamin D toxicosis) may be very important.

Atelectasis (Congenital and Acquired): The term atelectasis means incomplete distention of alveoli and is used to describe lungs that have failed to expand with air at the time of birth (congenital atelectasis) or lungs that have collapsed after inflation has taken place (acquired atelectasis or alveolar collapse) (Figs. 9-34 and 9-35).

During fetal life, lungs are not fully distended, contain no air, and are partially filled with a locally produced fluid known as fetal lung fluid. Not surprisingly, lungs of aborted and stillborn fetuses sink when placed in water, whereas those from animals that have breathed float. At the time of birth, fetal lung fluid is rapidly reabsorbed and replaced by inspired air, leading to the normal distention of alveoli. Congenital atelectasis occurs in newborns who fail to inflate their lungs after taking their first few breaths of air; it is caused by obstruction of airways, often as a result of aspiration of amniotic fluid and meconium (described in the section on Meconium Aspiration Syndrome) (see Fig. 9-34). Congenital atelectasis also develops when alveoli cannot remain distended after initial aeration because of an alteration in quality and quantity of pulmonary surfactant produced by type II pneumonocytes and Clara cells. This form infant of congenital atelectasis is referred to in human neonatology as infant respiratory distress syndrome (IRDS) or as hyaline membrane disease because of the clinical and microscopic features of the disease. It commonly occurs in babies who are premature or born to diabetic or alcoholic mothers and is occasionally found in animals, particularly in foals and piglets. The pathetic, gasping attempts of affected foals and pigs to breathe have prompted the use of the name “barkers”; foals that survive may have brain damage from cerebral hypoxia (see Chapter 14) and are referred to as “wanderers,” owing to their aimless behavior and lack of a normal sense of fear.

Acquired atelectasis is much more common and occurs in two main forms: compressive and obstructive (see Fig. 9-35). Compressive atelectasis has two main causes: space-occupying masses in the pleural cavity, such as abscesses and tumors, or transferred pressures, such as that caused by bloat, hydrothorax, hemothorax, chylothorax, and empyema (Fig. 9-36). Another form of compressive atelectasis occurs when the negative pressure in the thoracic cavity is lost because of pneumothorax. This form generally has massive atelectasis and thus is also referred to as lung collapse.

Obstructive (absorption) atelectasis occurs when there is a reduction in the diameter of the airways caused by mucosal edema and inflammation, or when the lumen of the airway is blocked by mucus plugs, exudate, aspirated foreign material, or lungworms (see Fig. 9-35). When the obstruction is complete, trapped air in the lung eventually becomes reabsorbed. Unlike the compression type, obstructive atelectasis often has a lobular pattern as a result of blockage of the airway supplying that lobule. This lobular appearance of atelectasis is more common in species with poor collateral ventilation, such as cattle and sheep. The extent and location of obstructive atelectasis depends largely on the size of the affected airway (large versus small) and on the degree of obstruction (partial versus complete).

Atelectasis also occurs when large animals are kept recumbent for prolonged periods, such as during anesthesia (hypostatic atelectasis). The factors contributing to hypostatic atelectasis are a combination of blood-air imbalance, shallow breathing, airway obstruction because of mucus and fluid that has not been drained from bronchioles and alveoli, and from inadequate local production of surfactant. Atelectasis can also be a sequel to paralysis of respiratory muscles and prolonged use of mechanical ventilation or general anesthesia in intensive care.

In general, the lungs with atelectasis appear depressed below the surface of the normally inflated lung. The color is generally dark blue and the texture is flabby or firm; they are firm if there is concurrent edema or other processes, such as can occur in ARDS or “shock” lungs (see the section on Pulmonary Edema). Distribution and extent vary with the process, being patchy (multifocal) in congenital atelectasis, lobular in the obstructive type, and of various degrees in between in the compressive type. Microscopically, the alveoli are collapsed or slitlike and the alveolar walls appear parallel and close together, giving prominence to the interstitial tissue even without any superimposed inflammation.

Pulmonary Emphysema: Pulmonary emphysema, often simply referred to as emphysema, is an extremely important primary disease in humans, whereas in animals, it is always a secondary condition resulting from a variety of pulmonary lesions. In human medicine, emphysema is strictly defined as an abnormal permanent enlargement of airspaces distal to the terminal bronchiole, accompanied by destruction of alveolar walls (alveolar emphysema). This definition separates it from simple air space enlargement or hyperinflation, in which there is no destruction of alveolar walls and which can occur congenitally (Down syndrome) or be acquired with age (aging lung, sometimes misnamed “senile emphysema”). The pathogenesis of emphysema in humans is still controversial, but current thinking overwhelmingly suggests that destruction of alveolar walls is largely the result of an imbalance between proteases released by phagocytes and antiproteases produced in the lung as a defense mechanism (the protease-antiprotease theory). The destructive process is markedly accelerated by any factor, such as cigarette smoking, pollution, or defects in the synthesis of antiproteases in humans, that increases the recruitment of macrophages and leukocytes in the lungs. This theory originated when it was found that humans with homozygous α₁-antitrypsin deficiency were remarkably susceptible to emphysema and that proteases (elastase) inoculated intratracheally into the lungs of laboratory animals produced lesions similar to those found in the disease. More than 90% of the problem relates to cigarette smoking, and airway obstruction is no longer considered to play a major role in the pathogenesis of emphysema in humans.

Primary emphysema does not occur in animals, and thus no animal disease should be called simply emphysema. In animals, this lesion is always secondary to obstruction of outflow of air or is agonal at slaughter. Secondary pulmonary emphysema occurs frequently in animals with bronchopneumonia, in which exudate plugging bronchi and bronchioles causes an airflow imbalance where the volume of air entering exceeds the volume leaving the lung. This airflow imbalance is often promoted by the so-called one-way valve effect caused by the exudate, which allows air into the lung during inspiration but prevents movement of air out of the lung during expiration.

Depending on the localization in the lung, emphysema can be classified as alveolar or interstitial. Alveolar emphysema characterized by distention and rupture of the alveolar walls, forming variably sized air bubbles in pulmonary parenchyma, occurs in all species. Interstitial emphysema occurs mainly in cattle, presumably because of their wide interlobular septa, and lack of collateral ventilation in these species does not permit air to move freely into adjacent pulmonary lobules. As a result, accumulated air penetrates the alveolar and bronchiolar walls and forces its way into the interlobular connective tissue, causing notable distention of the interlobular septa. It is also suspected that forced respiratory movements predispose to interstitial emphysema when air at high pressure breaks into the loose connective tissue of the interlobular septa (Fig. 9-37). Sometimes these bubbles of trapped air in alveolar or interstitial emphysema become confluent, forming large (several centimeters in diameter) pockets of air that are referred to as bullae (singular: bulla); the lesion is then called bullous emphysema. This lesion is not a specific type of emphysema and does not indicate a different disease process, but rather is a larger accumulation of air at one focus. In the most severe cases, air moves from the interlobular septa into the connective tissue surrounding the main stem bronchi and major vessels (bronchovascular bundles) and from here it leaks into the mediastinum, causing pneumomediastinum first, and eventually exits via the thoracic inlet into the cervical and thoracic subcutaneous tissue causing subcutaneous emphysema.

It should be noted that mild and even moderate alveolar emphysema is difficult to judge at necropsy and by light microscopy unless special techniques are used to prevent collapse of the lung when the thorax is opened. These techniques include plugging of the trachea or intratracheal perfusion of fixative (10% neutral-buffered formalin) before the thorax is opened to prevent collapse of the lungs. Important diseases that cause secondary pulmonary emphysema in animals include small airway obstruction (such as heaves) in horses and pulmonary edema and emphysema (fog fever) in cattle (see Fig. 9-37) and exudates in bronchopneumonia.

Hyperemia and Congestion: Hyperemia is an active process that is part of acute inflammation, whereas congestion is the passive process resulting from decreased outflow of venous blood, as occurs in acute congestive heart failure (Fig. 9-38). In the early acute stages of pneumonia, the lungs appear notably red, and microscopically, blood vessels and capillaries are engorged with blood from hyperemia. Pulmonary congestion is most frequently caused by heart failure, which results in stagnation of blood in pulmonary vessels, leading to edema and egression of erythrocytes into the alveolar spaces. As with any other foreign particle, erythrocytes in alveolar spaces are rapidly phagocytosed (erythrophagocytosis) by pulmonary alveolar macrophages. When extravasation of erythrocytes is severe, large numbers of macrophages with brown cytoplasm may accumulate in the bronchoalveolar spaces. The brown cytoplasm is the result of accumulation of considerable amounts of hemosiderin; these macrophages filled with iron pigment (siderophages) are generally referred to as heart failure cells (Fig. 9-39). The lungs of animals with chronic heart failure usually have a patchy red appearance with foci of brown discoloration because of accumulated hemosiderin. In severe and persistent cases of heart failure, the lungs fail to collapse because of edema and pulmonary fibrosis. Terminal pulmonary congestion (acute) is frequently seen in animals euthanized with barbiturates and should not be mistaken for an antemortem lesion.

Hypostatic congestion is another form of pulmonary congestion that results from the effects of gravity and poor circulation on a highly vascularized tissue, such as the lung. This type of gravitational congestion is characterized by the increase of blood in the lower side of the lung, particularly the lower lung, of animals in lateral recumbency, particularly horses and cattle. The affected portions of the lung appear dark red and can have a firmer texture. In animals and particularly humans that have been prostrated for extended periods of time, hypostatic congestion may be followed by hypostatic edema, and hypostatic pneumonia as edema interferes locally with the bacterial defense mechanisms.

Pulmonary Hemorrhage: Pulmonary hemorrhages can occur as a result of trauma, coagulopathies, pulmonary thromboembolism from jugular thrombosis or from embolisms of exudate from a hepatic abscess that has eroded the wall and ruptured into the caudal vena cava (cattle), disseminated intravascular coagulation (DIC), vasculitis, or sepsis. A gross finding, often confused with intravital pulmonary hemorrhage is the result of severing both the trachea and carotid arteries simultaneously at slaughter. Blood is aspirated into the transected trachea and thence into the lungs and there forms a random pattern of scattered irregular red foci (1 to 10 mm), in one to more lobes. These red foci are readily visible on both the pleural and cut surfaces of the lung and free blood is visible in the lumens of bronchi and bronchioles.

Rupture of a major pulmonary vessel with resulting massive hemorrhage occurs occasionally in cattle when a growing abscess in a lung invades and disrupts the wall of a major pulmonary artery or vein (Fig. 9-40). In most cases, animals die rapidly, often with spectacular hemoptysis, and on postmortem examination, bronchi are filled with blood (see Fig. 9-40).

Exercise-induced pulmonary hemorrhage (EIPH) is a specific form of pulmonary hemorrhage in racehorses after exercise and clinically is characterized by epistaxis. Because only a small percentage of horses with bronchoscopic evidence of hemorrhage have clinical epistaxis, it is likely that EIPH goes undetected in many cases. The pathogenesis is still controversial, but current literature suggests laryngeal paralysis, bronchiolitis, extremely high pulmonary vascular and alveolar pressures during exercise, alveolar hypoxia, and preexisting pulmonary injury as possible causes. EIPH is seldom fatal; postmortem lesions in the lungs of horses that have been affected with several episodes of hemorrhage are characterized by large areas of dark brown discoloration, largely in the caudal lung lobes. Microscopically, lesions are alveolar hemorrhages, abundant alveolar macrophages containing hemosiderin (siderophages), and mild fibrosis of the alveolar walls.

Pulmonary Edema: In normal lungs, fluid from the vascular space slowly but continuously passes into the interstitial tissue where it is rapidly drained by the pulmonary and pleural lymphatic vessels. Recent investigations demonstrated that alveolar fluid clearance across the alveolar epithelium is also a major mechanism of fluid removal from the lung. Edema develops when the rate of fluid transudation from pulmonary vessels into interstitium or alveoli exceeds that of lymphatic and alveolar removal (Fig. 9-41). Pulmonary edema can be physiologically classified as cardiogenic (hydrostatic; hemodynamic) and noncardiogenic (permeability) types.

Hydrostatic (cardiogenic) pulmonary edema develops when there is an elevated rate of fluid transudation because of increased hydrostatic pressure in the vascular compartment or decreased osmotic pressure in the blood. Once the lymph drainage has been overwhelmed, fluid accumulates in the perivascular spaces, causing distention of the bronchovascular bundles and alveolar interstitium, and eventually leaks into the alveolar spaces. Causes of hemodynamic pulmonary edema include congestive heart failure (increased hydrostatic pressure); iatrogenic fluid overload; disorders in which blood osmotic pressure is reduced, such as in the hypoalbuminemia seen in some hepatic diseases; nephritic syndrome; and protein-losing enteropathy. Hemodynamic pulmonary edema also occurs when lymph drainage is impaired, generally secondary to neoplastic invasion of lymph vessels.

Permeability edema (inflammatory) occurs when there is excessive opening of endothelial gaps or damage to the cells that constitute the blood-air barrier (endothelial cells or type I pneumonocytes). This type of edema is an integral and early part of the inflammatory response, primarily because of the effect of inflammatory mediators, such as leukotrienes, platelet-activating factor (PAF), cytokines, and vasoactive amines released by neutrophils, macrophages, mast cells, lymphocytes, endothelial cells, and type II pneumonocytes. These inflammatory mediators increase the permeability of the blood-air barrier. In other cases, permeability edema results from direct damage to the endothelium or type I pneumonocytes, allowing plasma fluids to move freely from the vascular space into the alveolar lumen (Fig. 9-42). Because type I pneumonocytes are highly vulnerable to some pneumotropic viruses (influenza, BRSV), toxicants (nitrogen dioxide [NO₂], sulfur dioxide [SO₂], hydrogen sulfide [H₂S], 3-methylindole), and particularly to free radicals, it is not surprising that permeability edema commonly accompanies many viral or toxic pulmonary diseases. A permeability edema also occurs when endothelial cells in the lung are injured by bacterial toxins, sepsis, ARDS, DIC, anaphylactic shock, milk allergy, paraquat toxicity, and adverse drug reactions.

The concentration of protein in edematous fluid is greater in permeability edema (exudate) than in hemodynamic edema (transudate); this difference has been used clinically in human medicine to differentiate one type of pulmonary edema from another. Microscopically, because of the higher concentration of protein, edema fluid in lungs with inflammation or damage to the blood-air barrier tends to stain more intensely eosinophilic than that of the hydrostatic edema from heart failure.

Grossly the edematous lungs—independent of the cause—are wet and heavy; the color varies, depending on the degree of congestion or hemorrhage; and fluid may be present in the pleural cavity. If edema is severe, bronchi and trachea contain considerable amounts of foamy fluid, which originates from the mixing of edema fluid and air (Fig. 9-43). On cut surfaces, the lung parenchyma oozes fluid like a wet sponge. In cattle and pigs that have distinct lobules, the lobular pattern becomes rather accentuated because of edematous distentions of lymphatic vessels in the interlobular septa and the edematous interlobular septum itself (Fig. 9-44). Severe pulmonary edema may be impossible to differentiate from peracute pneumonia; this fact is not surprising because pulmonary edema occurs in the very early stages of inflammation. Careful observation of the lungs at the time of necropsy is critical because diagnosis of pulmonary edema cannot be reliably performed microscopically. This is due in part to the loss of the edema fluid from the lungs during fixation with 10% neutral-buffered formalin and in part to the fact that the fluid itself stains very poorly or not at all with eosin because of its low protein content (hemodynamic edema). A protein-rich (permeability) edema is easier to visualize microscopically because it is deeply eosinophilic in hematoxylin and eosin (H&E)-stained sections (see Fig. 9-42), particularly if a fixative, such as Zenker’s solution, which precipitates protein, is used.

Acute Respiratory Distress Syndrome: Acute (adult) respiratory distress syndrome (ARDS; shock lung) is an important condition in humans and animals characterized by pulmonary hypertension, intravascular aggregation of neutrophils in the lungs, diffuse alveolar damage, permeability edema, and formation of hyaline membranes, which are a mixture of plasma proteins, fibrin, surfactant, and cellular debris from necrotic pneumonocytes. The pathogenesis is complex and multifactorial but in general terms can be defined as diffuse alveolar damage that results from lesions in distant organs, from generalized systemic diseases, or from direct injury to the lung. Sepsis, major trauma, aspiration of gastric contents, extensive burns, and pancreatitis are some of the disease entities known to trigger ARDS. All these conditions provoke “hyperreactive macrophages” to directly or indirectly generate overwhelming amounts of cytokines (mainly TNF-α, interleukin [IL]-1, IL-6, and IL-8). Some of these cytokines prime neutrophils previously recruited in the lung capillaries and alveoli to release enzymes and free radicals, thus causing diffuse endothelial and alveolar damage that culminates in a fulminating pulmonary edema (Fig. 9-45). ARDS occurs in domestic animals and explains why pulmonary edema is one of the most common lesions found in many animals dying of sepsis, toxemia, aspiration of gastric contents, and pancreatitis, for example. A familial form of ARDS has been reported in Dalmatians. The pulmonary lesions in this syndrome are further discussed in the sections on Interstitial Pneumonia and Aspiration Pneumonia in Dogs.

Neurogenic pulmonary edema is another distinctive but poorly understood form of life-threatening lung edema in humans that follows increased intracranial pressure (i.e., head injury, brain edema, brain tumors, or cerebral hemorrhage). This type of pulmonary edema can be experimentally reproduced in laboratory animals by injecting fibrin into the fourth ventricle. It involves both hemodynamic and permeability pathways presumably from massive sympathetic stimulation and overwhelming release of catecholamines. Neurogenic pulmonary edema has sporadically been reported in animals with brain injury or severe seizures or after severe stress and excitement.

Pulmonary Embolisms: With its vast capillary bed and position in the circulation, the lung acts as a safety net to catch emboli before they reach the brain and other tissues. However, this positioning is often to its own detriment. The most common pulmonary emboli in domestic animals are thromboemboli, septic (bacterial) emboli, fat emboli, and tumor cell emboli.

Pulmonary thromboembolism generally originates from a thrombus present elsewhere in the venous circulation (Fig. 9-46). Fragments released inevitably reach the lungs and become trapped in the pulmonary vasculature (Fig. 9-47). Small sterile thromboemboli are generally of little clinical or pathologic significance because they can be rapidly degraded and disposed of by the fibrinolytic system. Parasites, such as Dirofilaria immitis and Angiostrongylus vasorum; endocrinopathies, such as hyperadrenocorticism and hypothyroidism; glomerulopathies; and hypercoagulable states can be responsible for pulmonary arterial thrombosis and pulmonary thromboembolism in dogs. Pieces of thrombi breaking free from a jugular, femoral, or uterine vein can cause pulmonary thromboembolism. Pulmonary thromboembolisms occur in heavy horses after prolonged anesthesia (deep vein thrombosis), recumbent cows (“downer cow syndrome”), or in any animal undergoing long-term intravenous catheterization in which thrombi build up in the catheter and then break off (see Fig. 9-47).

Septic emboli, pieces of thrombi contaminated with bacteria or fungi and broken free from infected mural or valvular thrombi in the heart and vessels, eventually become entrapped in the pulmonary circulation. These emboli originate most commonly from bacterial endocarditis (right side) and jugular thrombophlebitis in all species, hepatic abscesses that have eroded and discharge their contents into the caudal vena cava in cattle, and septic arthritis and omphalitis in farm animals (see Figs. 9-46 and 9-47). When present in large numbers, septic emboli may cause unexpected death because of massive pulmonary edema; survivors generally develop pulmonary arteritis and thrombosis and embolic (suppurative) pneumonia, which may lead to pulmonary abscesses.

Fat emboli can form after bone fractures or surgical interventions of bone. These are not as significant a problem in domestic animals as they are in humans. Brain emboli (i.e., pieces of brain tissue) in the pulmonary vasculature reported in severe cases of head injury in humans have recently been recognized in the bovine lung after strong pneumatic stunning at slaughter (captive bolt). Although obviously not important as an antemortem pulmonary lesion, brain emboli are intriguing as a potential risk for public health control of bovine spongiform encephalopathy (BSE). Hepatic emboli formed by circulating pieces of fragmented liver occasionally become trapped in the pulmonary vasculature after severe abdominal trauma and hepatic rupture. Tumor emboli (e.g., osteosarcoma and hemangiosarcoma in dogs and uterine carcinoma in cattle) can be numerous and striking and the ultimate cause of death in malignant neoplasia. In experimental studies, cytokines released during pulmonary inflammation are chemotactic for tumor cells and promote pulmonary metastasis.

Pulmonary (Lung) Infarcts: Because of a dual arterial supply to the lung, pulmonary infarction is rare and generally asymptomatic. However, pulmonary infarcts can be readily caused when pulmonary thrombosis and embolism are superimposed on an already compromised pulmonary circulation such as occurs in congestive heart failure. It also occurs in dogs with torsion of a lung lobe (Fig. 9-48). The gross features of infarcts vary considerably, depending on the stage, and they can be red to black, swollen, firm, and cone or wedge shaped, particularly at the lung margins. In the early acute stage, microscopic lesions are severely hemorrhagic, and this is followed by necrosis. In 1 to 2 days, a border of inflammatory cells develops, and a few days later, a large number of siderophages are present in the necrotic lung. If sterile, pulmonary infarcts heal as fibrotic scars; if septic, an abscess may form surrounded by a thick fibrous capsule.

Bronchi: The patterns of necrosis, inflammation, and repair in intrapulmonary bronchi are similar to those previously described for the nasal and tracheal epithelium. In brief, injury to ciliated bronchial epithelium may result in degeneration, detachment, and exfoliation of necrotic cells. Under normal circumstances, cellular exfoliation is promptly followed by inflammation, mitosis, cell proliferation, cell differentiation, and finally by repair (Fig. 9-49). Depending on the type of exudate, bronchitis can be fibrinous, catarrhal, purulent, fibrinonecrotic (diphtheritic), and sometimes granulomatous. When epithelial injury becomes chronic, production of mucus is increased via goblet cell hyperplasia (chronic catarrhal inflammation). This form of chronic bronchitis is well illustrated in habitual smokers who continually need to cough out excessive mucus secretions (sputum). Unfortunately, in some cases, excessive mucus cannot be effectively cleared from airways, which leads to chronic obstructive bronchitis and emphysema (see Fig. 9-49). Chronic bronchial irritation causes squamous metaplasia of highly functional but vulnerable ciliated epithelium to nonfunctional, but more resistant, squamous epithelium. Squamous metaplasia has a calamitous effect on pulmonary clearance because it causes a structural loss and functional breakdown of portions of the mucociliary escalator. Hyperplasia of bronchial glands occurs frequently in chronic bronchitis, which translates to an increase of the Reid Index (bronchial-gland to bronchial-wall ratio). This index is less than 40% in the healthy human lung and in the lungs of most domestic species, except for cats, which generally have an index higher than 40%. The term airway remodeling encompasses all the structural changes that accompany chronic bronchitis such as hypertrophy and hyperplasia of smooth muscle, submucosal glands, and goblet cells; fibrosis; and increased bronchial vascularity.

Bronchiectasis is one of the most devastating sequelae to chronic remodeling of the bronchi. It consists of a pathologic and permanent dilation of a bronchus with rupture of the bronchial wall as a result of obstruction or chronic inflammation. Destruction of walls occurs in part when proteolytic enzymes and oxygen radicals released from phagocytic cells during chronic inflammation degrade and weaken the smooth muscle and cartilage that help to maintain normal bronchial diameter (Fig. 9-50). Bronchiectasis may be saccular when destruction affects only a small localized portion of the bronchial wall or cylindric when destruction involves a large segment of a bronchus. Grossly, bronchiectasis is manifested by prominent lumps in the lungs (bosselated appearance or having rounded eminences) resulting from distention of bronchi with exudate, which results in a concurrent obstructive atelectasis of surrounding parenchyma (Fig. 9-51). The cut surfaces of dilated bronchi are filled with purulent exudates; for this reason, bronchiectasis is often mistaken for pulmonary abscesses. Careful inspection, usually requiring microscopic examination, confirms that exudate is contained and surrounded by remnants of a bronchial wall lined by squamous epithelium and not by a pyogenic membrane (connective tissue) as it is in the case of a pulmonary abscess. The squamous metaplasia further interferes with the normal function of the mucociliary escalator.

Bronchioles: The epithelial lining of the bronchiolar region (transitional zone) is exquisitely susceptible to injury, particularly to that caused by some respiratory viruses (PI-3, adenovirus, BRSV, or canine distemper), oxidant gases (NO₂, SO₂, or ozone [O₃]), and toxic substances (3-methylindole, paraquat). The precise explanation as to why bronchiolar epithelium is so prone to injury is still not clear, but it is presumably due in part to (1) its high vulnerability to oxidants and free radicals; (2) the presence of Clara cells rich in mixed-function oxidases, which locally generate toxic metabolites; and (3) the tendency for pulmonary alveolar macrophages and leukocytes to accumulate in this region of the lungs. Depending on the types of injury and inflammatory response, bronchiolitis is classified as necrotizing, suppurative, catarrhal (mucous metaplasia), or granulomatous.

Alveoli: Because of their extremely delicate structure, alveoli are quite vulnerable to injury once the local defense mechanisms have been overwhelmed. The alveolar wall is a thin membrane formed by a core of interstitium supporting an extensive network of alveolar capillaries. Fibroblasts (septal cells), myofibroblasts, collagen, elastic fibers, and few interstitial macrophages and mast cells constitute the alveolar interstitium. The wall of the alveolar capillaries facing the airspace is remarkably thin and has three layers composed of vascular endothelium, basal lamina, and alveolar epithelium. These three layers of the alveolar capillaries constitute what is customarily referred to as the blood-air barrier (see Fig. 9-7). The epithelial side of the alveolus is primarily lined by rather thin type I pneumonocytes, which are arranged as a very delicate continuous membrane extending along the alveolar surface (see Fig. 9-7). Type I pneumonocytes are particularly susceptible to noxious agents that reach the alveolar region either aerogenously or hematogenously. Injury to type I pneumonocytes rapidly causes swelling and vacuolation of these cells. When cellular damage has become irreversible, type I cells detach, resulting in denudation of the basement membrane, increased alveolar permeability, and alveolar edema. Alveolar repair is possible as long as the basement membrane remains intact and lesions are not complicated by further injury or infection. Within 3 days, cuboidal type II (granular) pneumonocytes, which are the precursor cells and more resistant to injury, undergo mitosis and provide a large pool of new undifferentiated cells (Fig. 9-54). These new cells repave the denuded alveolar basement membrane and finally differentiate in type I pneumonocytes. When alveolar injury is diffuse, proliferation of type II pneumonocytes becomes so spectacular that the microscopic appearance of the alveolus resembles that of a gland or fetal lung; the lesion has been termed epithelialization or fetalization. Although it is part of the normal alveolar repair, hyperplasia of type II pneumonocytes can interfere in gas exchange and cause hypoxemia. In uncomplicated cases, type II pneumonocytes eventually differentiate into type I pneumonocytes, thus completing the last stage of alveolar repair. In some forms of chronic interstitial lung injury the surface of the alveolar basement membrane could become populated with migrating bronchiolar cells, a process known as alveolar bronchiolization or lambertosis. In severe cases, lambertosis, a metaplastic change, can be mistaken microscopically with alveolar adenomas.

Type I pneumonocytes are one of the three structural components of the blood-air barrier, so when these epithelial cells are damaged, there is an increase in alveolar capillary permeability and transient leakage of plasma fluid, proteins, and fibrin into the alveolar lumen. Under normal circumstances, these fluids are rapidly cleared from the alveolus by alveolar and lymphatic absorption, and necrotic pneumonocytes (type I) and fibrin strands are phagocytosed and removed by pulmonary alveolar macrophages. When there is persistent and severe injury, fibroblasts and myofibroblasts may proliferate in the alveolar walls (alveolar interstitium), causing alveolar fibrosis, whereas in other forms of severe injury, fibroblasts and myofibroblasts actively migrate from the interstitium into the alveolar spaces, causing intraalveolar fibrosis. These two types of alveolar fibrosis are most commonly seen in toxic and allergic pulmonary diseases, and this alveolar fibrosis has a devastating effect on lung function.

Endothelial cells are also major players in the normal and abnormal physiology of the alveolus. These cells trap and share circulating antigens with intravascular and interstitial macrophages. The junction between alveolar endothelial cells is not as tight as that of the type I pneumonocytes, allowing some movement of fluid and small size molecular weight proteins into the alveolar interstitium. Endothelial cells maintain an intimate cell contact with erythrocytes and leukocytes passing through the lung, since the lumen of alveolar capillaries is slightly smaller (5.0 µm) than the diameter of red and white blood cells. Erythrocytes are easily deformable, so their transit time through the alveolar capillaries is shorter than leukocytes, which are less deformable cells. This longer transit time of leukocytes and their close cellular contact with alveolar endothelial cells has major impact in lung inflammation and ARDS.

On a minute-to-minute basis, the pulmonary defense mechanisms deal effectively with noxious stimuli and mild tissue injury without the need for an inflammatory response. However, if normal defense mechanisms are ineffective or insufficient (overwhelmed), the inflammatory process is rapidly turned on as a second line of defense.

Alveolar Filling Disorders: Alveolar filling disorders are a heterogeneous group of lung diseases characterized by accumulation of various chemical compounds in the alveolar lumens. The most common are alveolar proteinosis in which the alveoli are filled with finely granular eosinophilic material; alveolar microlithiasis in which the alveoli contain numerous concentric calcified “microliths” or “calcospherites.” A similar but distinct concretion is known as corpora amylacea, which is an accumulation of cholesterol (cholesterol pneumonitis) or lipids (endogenous lipid pneumonia; see the section on Other Pneumonias of Cats). There is often little host response, and in many cases, it is only an incidental finding. Some of the alveolar filling disorders originate from inherited metabolic defects in which alveolar cells (epithelial or macrophages) cannot properly metabolize or remove lipids or proteins while others result from an excessive synthesis of these substances in the lung.