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Tufts OpenCourseware
Author: Angie Warner, D.V.M.,D.Sc.

1. Physiology of the Pulmonary Circulation and Pulmonary Edema

1.1. The Normal Pulmonary Circulation

  • The pulmonary circulation has low pressure (systolic 25 mmHg) because:
    • the right ventricle generates less pressure than the left
    • the vessels are normally thin walled and distensible
  • The volume is normally low, but can increase tremendously (due to the distensibility).
  • Regional pulmonary artery pressure (gravity dependent) and alveolar pressure determine regional pulmonary flow.
    • pulmonary perfusion becomes more homogeneous during exercise
  • Bronchial circulation supplies trachea and all airways, vascular bundles, nerves, lymph nodes, and visceral pleura.
    • venous drainage is partly through pulmonary veins, and anastomoses between the two systems can develop in areas of tissue disruption or inflammation

1.2. Control of Pulmonary Circulation

  • The pulmonary endothelium synthesizes and releases both constricting and relaxing factors.
    • Nitric oxide (NO) is produced by pulmonary endothelial cells and mediates vascular relaxation
    • pulmonary endothelial injury can result in abnormal vasoactive function
  • PGI2 and PAF are potent pulmonary vasodilators.
  • Arachidonic acid metabolites thromboxane A2 and LTC4 and D4 are potent vasoconstrictors.
  • Pulmonary vessels constrict in response to hypoxia, and PAO2 is the primary determinant of pulmonary vascular resistance.
    • this response should direct blood flow to better ventilated areas
    • LTC4 and D4 are likely mediators of hypoxic constriction, and oxygen radicals or peroxide may also act as a mediator through control of transmembrane Ca flux
  • Pulmonary Metabolic Function
    • Pulmonary endothelial cells actively metabolize many biologically active substances prior to their delivery to the general circulation
    • Vasoactive agents such as polypeptides (bradykinin, angiotensin), biogenic amines (serotonin, norepinephrine), and arachidonic acid metabolites (prostacyclin, thromboxane) are metabolized
    • Pulmonary endothelial cells also synthesize and release numerous growth factors when perturbed
      • platelet-derived growth factor and epidermal growth factor
      • heparin-like growth inhibitory factor
      • balance between proliferative and antiproliferative factors is critical and can be easily altered
    • Pulmonary endothelial cells synthesize vasoactive agents that act locally: PAF, PGI2, and NO
  • Mechanisms of Pulmonary Edema
    • Capillary fluid flux depends on relative hydrostatic pressure, oncotic pressure, and permeability.
    • Qf = K [(Pc Pi) ó (π c – πi) ]
      • Qf = filtration rate
      • Pc = cap. hydrostatic P
      • c = cap. protein oncotic P
      • K = filtration coefficient
      • σ = reflection coefficient (permeability index)
      • Pi = interstitial hydrostatic P
      • i = interstitial protein oncotic P
    • Pc is normally low, but increases with inadequate left ventricular function (cardiogenic pulmonary edema)
      • as fluid leaks out of capillaries, Pi rises and tends to limit the process
      • Pi is lowest near vessels and airways, thus fluid tends to drain into these areas and away from the gas exchange region
    • c tends to hold fluid in capillaries unless there is serious hyproteinemia
    • Altered permeability (ó) occurs because of epithelial or endothelial cell injury and loss of barrier integrity (ARDS or acute lung injury)
      • fluid extruded from capillaries in this situation has high osmotic P, because the barrier to high molecular weight molecule passage has been lost
      • i tends to increase, but will not act to limit fluid loss from capillaries
    • Pulmonary lymphatics drain fluid lost from capillaries and frank edema occurs when this reserve for fluid drainage is overwhelmed

2. Pathophysiology of Pulmonary Hypertension

2.1. Experimental Models and Pathological Changes

  • Pulmonary vasoconstriction is a consistent acute response to stimuli that induce inflammation and injury.
  • A number of experimental models have been used to determine the chronic changes that lead from reversible vasoconstriction to persistent pulmonary hypertension.
    • hyperbaric oxygen, chronic endotoxemia, monocrotaline
  • Pathological changes include thickening of medial smooth muscle, extension of smooth muscle distally to normally nonmuscular arteries, and narrowing and occlusion of distal arteries.
    • precursor cells within the intima develop into smooth muscle cells
  • Downregulation of endothelial-derived relaxing and antiproliferative factors (NO) and upregulation of endothelial-derived vasoconstrictive and mitogenic factors occurs, changing the balance of parameters regulating vascular tone.

2.2. Bovine Brisket Disease

  • Pulmonary arterial hypertension, congestive heart failure, and edema involving the thorax, abdomen and subcutaneous tissue of the brisket. forelimbs and abdomen.
  • This occurs in cattle pastured at high altitude, presumably as a sequelae of hypoxic pulmonary vasoconstriction and chronic pulmonary hypertension.
    • inadequate right ventricular ejection due to vascular resistance (cor pulmonale)
  • Endothelial cell injury with permeability changes may also contribute to edema.
  • Not all cattle at high altitude are affected, individual genetic susceptibility is also important.

2.3. Equine Exercise Induced Pulmonary Hemorrhage (EIPH)

  • Pulmonary hemorrhage in racing horses and polo ponies after strenuous exercise characterized by pulmonary hypertension, alveolar region edema, pulmonary capillary rupture, and intra-alveolar hemorrhage.
  • Diagnosis is by observation of epistaxis, endoscopy, trastracheal aspiration, or bronchoalveolar lavage (detection of hemosiderophages).
    • endoscopy demonstrates many cases that do not show epistaxis
  • Evidence of pulmonary hemorrhage can be seen in 43 75% of TB, 26-77% of Standardbreds, and 62% of Quarter horses horses after racing.
    • this is a repeatable event in one animal and often increases with age
    • affects performance due to alveolar edema, irritation and inflammation
    • repeated bouts result in fibrosis and sustained inflammation
  • Bleeding occurs in the caudo dorsal region of the lungs, and appears to be a result of high pulmonary vascular pressures (>120 mmHg) that occur in the horse during strenuous exercise.
    • stress failure of capillaries occurs with endothelial disruption, collection of blood in the interstitium and consequent inflammation
  • Prevention and treatment include use of diuretics (furosemide), which decrease pulmonary hypertension and decrease blood volume, and nasal dilator strips that reduce nasal resistance.
  • Inhaled nitric oxide (NO) has been used to reduce pulmonary artery pressure, but more severe bleeding occurs.

3. Pulmonary Embolism

3.1. Pathophysiology

  • Pulmonary embolism of large thrombi formed in veins of the lower limbs is a common clinical event in humans that results in 500,000 deaths/year thus, it has been well studied.
    • other embolic sources are air, fat, tumor cells, amnionic fluid, foreign bodies
  • Large pulmonary emboli that lodge in major PA branches vastly increase dead space and increase V/Q ratio.
    • increased flow to non obstructed areas further alter V/Q and results in hypoxemia, which induces vasoconstriction
  • Pulmonary emboli result in local release of inflammatory mediators that enhance pulmonary vasoconstriction and increase permeability.
  • Pulmonary emboli are less common in veterinary than human patients, but any condition causing stasis of blood flow, hypercoagulability, or vascular endothelial injury will predispose to thrombus formation.

3.2. Bovine Septic Thromboembolism (Caudal Vena Caval Thrombosis)

  • Occurs most often in adult cattle who develop hepatic abscesses secondary to rumenitis. Ruminal acidosis from feeding highly fermentable grain predisposes to rumen wall invasion and colonization by rumen bacteria.
  • Hepatic abscesses develop from portal vein emboli containing bacteria, and then septic emboli metastasize further to the lungs. Pulmonary arteritis and aneurysms develop, and aneurysms may rupture, causing fatal pulmonary hemorrhage.
    • The organism most commonly involved is Fusobacterium necrophorum, a gram negative pleomorphic rod and normal inhabitant of the GI tract.
  • Canine Dirofilariasis and Pulmonary Vascular Pathology.
    • Characteristic pulmonary arterial lesions are caused by 5th stage juveniles that develop in pulmonary artery branches
      • the right caudal is usually most severely affected due to relative flow pattern (i.e., parasite arrival is an embolic phenomenon
    • Two types of pulmonary arterial lesions develop:
      • intimal proliferation due to effects of live parasites
      • thrombosis due to dead parasites
  • Intimal proliferative changes begin during the prepatent period in smallest muscular branches (i.e., downstream from parasites) of those vessels occupied by worms.
    • intimal thickening progresses to ridges and villi that protrude into the lumen and predispose to platelet deposition
    • toxins or inflammatory mediators are suspected to contribute to these downstream lesions
  • Inflammatory response to live parasites involves PMN and eosinophil and platelet activation by heartworm surface proteins. Pulmonary parenchymal changes include acute inflammation followed by fibrosis with collagen deposition in the interstitium.
  • Thrombotic lesions form as dead worm fragments act as a nidus, and local infarcts cause vessel wall necrosis and rupture.
  • Pulmonary hypertension is an important aspect of this disease due to intravascular proliferative lesions, inflammatory mediated vasoconstriction, and decreased endothelial NO production.
    • chronic pulmonary hypertension inevitably contributes to right ventricular dilatation and hypertrophy
  • Cats are a susceptible host, but the worm burden is less and adults live a shorter time. Pulmonary disease is a more prominent aspect than in dogs. Cats often present with cough and dyspnea. Microfilaremia is uncommon.

4. References

  • Amis TC, et al. Nasal vestibule wall elasticity: interactions with a nasal dilator strip. J Appl Physiol 86: 1638-1643, 1999.
  • Dillon AR. Heartworm disease in cats and dogs: the difference is in the host. Suppl Compend Cont Ed Pract Vet 21: 36-40, 1999.
  • Erickson HH, et al. Effect of furosemide on pulmonary blood flow distribution in resting and exercising horses. J Appl Physiol 86: 2034-2043m 1999.
  • Jensen R, et al. Brisket disease in yearling feedlot cattle. J Am Vet Med Assoc 169: 515 517, 1976.
  • Kirton OC, R Jones. Rat pulmonary artery restructuring and pulmonary hypertension induced by continuous E. coli endotoxin infusion. Lab Invest 56: 198 210, 1987.
  • Kulik TJ, JE Lock. Leukotrienes and the immature pulmonary circulation. Am Rev Respir Dis 136: 220 222, 1987.
  • LaRue MJ, Murtaugh RJ. Pulmonary thromboembolism in dogs: 47 cases (1986-1987). J Am Vet Med Assoc 197:1368-1372. 1990.
  • Manohar M. Furosemide attenuates the exercise-induced increase in pulmonary artery wedge pressure in horses. Am J Vet Res 54: 952-958, 1993.
  • Mills PC, et al. Nitric oxide and exercise in the horse. J Physiol (London) 15: 863-874, 1996.
  • Nagaraja TG, Laudert SB, Parrott JC. Liver abscess in feedlot cattle. Part I. Causes, pathogenesis, pathology, and diagnosis. Compend Cont Ed Pract Vet Sept 1996:S230-S241.
  • Snapper JR, KL Brigham. Pulmonary edema. Hosp Pract pp 87 101, May 15, 1986.
  • Weir EK, JT Reeves. Pulmonary Vascular Physiology and Pathophysiology, Marcel Dekker, Inc, New York, 1989.