JPC SYSTEMIC PATHOLOGY

RESPIRATORY SYSTEM

September 2023

P-T02 (NP)

 

Signalment (JPC #1460187): Rhesus macaque

 

HISTORY: This animal was used in an experimental pulmonary research study.

 

HISTOPATHOLOGIC DESCRIPTION: Lung: Multifocally, over 90% of alveolar septa are expanded by eosinophilic homogenous edema fluid, eosinophilic fibrillar material (fibrin), and few neutrophils, macrophages, lymphocytes, and plasma cells. There is necrosis and loss of type I pneumocytes. Alveoli are multifocally frequently lined by cuboidal epithelial cells (type II pneumocyte hyperplasia), which occasionally form micropapillary projections into alveolar lumina. Alveolar lumina occasionally contain an exudate composed of increased numbers of macrophages and fewer neutrophils mixed with edema, minimal hemorrhage, and fibrin. Multiple contiguous alveoli coalesce and are expanded by clear space (emphysema), or are consolidated (atelectasis). The bronchiolar epithelium is hyperplastic, piled up to 4 layers thick. There is multifocal anthracosilicosis and perivascular, peribronchiolar, and pleural edema and fibrin exudation.

 

MORPHOLOGIC DIAGNOSIS: Lung: Pneumonia, interstitial, fibrinoproliferative, subacute, diffuse, marked, with type II pneumocyte hyperplasia and alveolar emphysema, Macaca mulatta, non-human primate.

 

ETIOLOGIC DIAGNOSIS: Pulmonary oxygen toxicosis

 

GENERAL DISCUSSION:  

• Oxygen levels of 85-100% can lead to damage of capillary endothelium, type I pneumocytes, and serofibrinous exudation in alveoli (i.e. diffuse alveolar damage)
• High partial pressure oxygen is toxic to the respiratory, cardiovascular, and 

digestive systems, with the lung being the most susceptible

• Oxygen is toxic to the lung in humans when FIO₂ administered is >0.60 at 1 atmosphere of pressure for >24 hours
• Oxygen toxicity is one of many processes resulting in acute lung injury (ALI) and the resulting histopathology of diffuse alveolar damage (DAD)
• Diffuse alveolar damage has three phases: 

• Acute exudative phase: Alveolar septa contain edema and are congested, infiltrated by macrophages and neutrophils, and lined by hyaline membranes
• Subacute proliferative phase: Type II pneumocyte hyperplasia is evident by 2-3 days post-injury
• Chronic fibrosing phase: Fibroblast invasion of affected alveoli forms granulation tissue-like fibrous tissue that’s incorporated into the alveolar septa; ongoing damage within the septa result in TGF-β-induced fibroblast recruitment and well-organized interstitial fibrosis evident by day 14

 

PATHOGENESIS:  

• Increased partial pressure of inhaled oxygen causes increased free radical formation, overwhelming host defense mechanisms including superoxide dismutase, glutathione peroxidase, catalase, bilirubin, and vitamins C and E
• Reactive oxygen species (ROS) and free radicals (superoxide, hydrogen 

peroxide, singlet oxygen, and hydroxyl radicals) cause cellular damage by lipid peroxidation, protein oxidation, and DNA strand breaks  

• Oxygen toxicity preferentially damages endothelial cells and type I pneumocytes due to paucity of oxygen radical scavenging mechanisms in these cells; type II pneumocytes proliferate in response to type I damage
• Influx of inflammatory cells, edema, activation of arachidonic acid cascade, and 

complement activation 

membranes

fibrin organizes, resulting in interstitial fibrosis

 

TYPICAL CLINICAL FINDINGS:

• Initially may be asymptomatic  
• Can progress to tracheobronchial irritation (coughing and substernal pain); later severe pulmonary edema causes dyspnea, cyanosis, and death

 

TYPICAL GROSS FINDINGS:  

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:  

• Acute lesions:  

• Perivascular, interstitial, and intra-alveolar hemorrhage, edema, and fibrin 
• Variable necrosis of pulmonary epithelium and type I pneumocytes
• Neutrophilic and histiocytic inflammation
• Hyaline membrane formation

• Chronic cases:

• Prominent type II pneumocyte hyperplasia with eventual organizing fibrosis

 

DIFFERENTIAL DIAGNOSIS:

• Acute respiratory distress syndrome (ARDS; shock lung)
• Diffuse pulmonary infections
• Intoxications (ozone, paraquat, nitrogen dioxide)

 

COMPARATIVE PATHOLOGY:  

• Domestic animals

• ARDS, caused by diffuse alveolar capillary damage, is characterized by rapid 

onset of dyspnea, tachypnea, tachycardia, cyanosis, and severe arterial hypoxia that is unresponsive to oxygen therapy, and progresses to multisystem organ failure

• Lab animals

• Neonatal rats, mice, and rabbits are resistant to oxygen toxicity  
• Adult rats have similar histological changes
• Pleural effusion is the hallmark of oxygen toxicity in the rat
• In rabbits there is reduced tracheal cilia concentration, discharge of goblet cell mucus, and slowed tracheal mucus velocity 
• Often necrosis of CNS neurons, cardiac myocytes, and renal tubular epithelium

 

REFERENCES:  

1. Caswell JL, Williams KJ. Respiratory System. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier; 2016:518.
2. Husain AN. The lung. In: Kumar V, Abbas AK, Fausto N, Aster JC, eds. Robbins and Cotran Pathologic Basis of Disease. 10th ed. Philadelphia, PA: Elsevier; 2021:676-678

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