Pathophysiology of pulmonary hypertension in acute lung injury

Abstract

Acute lung injury (ALI) and acute respiratory distress syndrome are characterized by protein rich alveolar edema, reduced lung compliance, and acute severe hypoxemia. A degree of pulmonary hypertension (PH) is also characteristic, higher levels of which are associated with increased morbidity and mortality. The increase in right ventricular (RV) afterload causes RV dysfunction and failure in some patients, with associated adverse effects on oxygen delivery. Although the introduction of lung protective ventilation strategies has probably reduced the severity of PH in ALI, a recent invasive hemodynamic analysis suggests that even in the modern era, its presence remains clinically important. We therefore sought to summarize current knowledge of the pathophysiology of PH in ALI.

Fig. 1.

Mechanistic diagram illustrating the pathway through the pulmonary circulation and factors that may contribute to pulmonary hypertension (PH). This figure represents the factors in acute lung injury (ALI) contributing to the raised pulmonary vascular resistance (PVR) measured proximally in the pulmonary artery, as illustrated distally throughout the pulmonary vascular tree. Activation of pulmonary microvascular endothelium leads to initiation of inflammation and intravascular coagulation (also see Figs. 2–4): intravascular microthrombi, fibrin, and intravascular sequestration of cells contribute to pulmonary capillary occlusion, and clots also form in larger vessels. Vascular tone is increased in muscular arterioles and veins due to hypoxic pulmonary vasoconstriction (HPV), in an attempt to maintain ventilation/perfusion matching. Additionally, an imbalance of vasoactive mediators (e.g., endothelin-1 is raised) contributes to an increase in vasomotor tone. An overall reduction in lung volume, edema, positive end-expiratory pressure (PEEP), and atelectasis causes extrinsic vessel compression (top white circles). Later, structural changes of pulmonary vascular remodeling occur, with increased thickness of the existing pulmonary arterial smooth muscle layer, and neomuscularization of previously nonmuscularized vessels; fibrous intimal proliferative lesions are also seen in small pulmonary arteries, veins, and lymphatics. Finally, postcapillary PH may result from any cause of raised left atrial pressure such as left ventricular (LV) diastolic dysfunction due to myocardial ischemia or sepsis. Some or all of these pathological factors may contribute to the increase in PVR that is characteristic of ALI. Pplat, alveolar plateau pressure; EC, endothelial cell.

Fig. 2.

Components of endothelial activation/dysfunction in acute lung injury (ALI). This schematic cartoon illustrates the components of endothelial activation including 1) endothelial cell-leukocyte interactions, 2) endothelial cell-platelet-neutrophil interactions, and 3) structural changes between endothelial cells. These are described sequentially in detail within the text. RBC, red blood cell; MLCK, myosin light chain kinases; PASMC, pulmonary artery smooth muscle cell.

Fig. 3.

Obliteration of the pulmonary microcirculation. Silicone casts from postmortem specimens illustrating obliteration of the pulmonary microcirculation in a patient 3 wk following onset of acute lung injury (A), compared with that from a patient without pulmonary disease (B). With thanks to Professor Warren Zapol.

Fig. 4.

Overview of processes leading to intravascular coagulation and inflammation at microvascular endothelial surface in ALI. A: activation of intravascular coagulation. Vascular injury initiates the tissue factor-driven extrinsic pathway to generate thrombin. Tissue factor (TF), usually hidden on the subendothelium, is upregulated on platelets, leukocytes, and on EC during inflammation. TF interacts with factor (F) Va to activate FIX and X, leading to prothrombin (P) activation, involving the formation of complexes between FVa and factor Xa, with subsequent thrombin (T) formation. Thrombin binds to protease-activated receptors (PARs) expressed on platelets and EC and has several functions, most importantly to enable formation of fibrin from fibrinogen and the subsequent stabilization of stable clot by activating FVIII. Thrombin also activates FV and FVIII from the intrinsic pathway, the function of which is to amplify coagulation. B: reduction in anticoagulants. Protein C dysfunction Thrombin usually binds thrombomodulin (TM) on the luminal side of the EC and the thrombin-TM complex converts protein C to activated protein C (APC). APC interacts with the endothelial cell protein C receptor (EPCR), and protein S, and acts as a natural anticoagulant by inactivating FVa and FVIIIa. APC is also thought to inhibit plasminogen activator inhibitor-type 1 (PAI-1) thus indirectly promoting fibrinolysis (see section C). In addition to its anticoagulant properties, aPC also has anti-inflammatory effects. These include inhibition of TNF-α production and blocking adhesion of leukocytes to selectins. In ALI, protein C levels are low, thereby resulting in both (intravascular and extravascular) coagulation and inflammation. C: reduction in fibrinolysis. Once a stable clot has formed, fibrinolysis occurs to break down stable clot through the actions of plasmin. Plasminogen is activated to form plasmin by tissue plasminogen activator (tPA), usually released slowly into blood by damaged EC to enable clot breakdown following vessel injury. Other plasminogen activators include urokinase, and FXII, XIIa and kallikrein. To balance this, the principle inhibitor of tPA and urokinase is plasminogen activator inhibitor-type 1 (PAI-1). During inflammation, there is evidence that cytokines such as TNF-α can stimulate the release of inhibitors of plasminogen activators, thus attenuating fibrinolysis.

Fig. 5.

Increased pulmonary vascular resistance at extremes of lung volumes. This figure represents measurements made in an animal lobe preparation in which the transmural pressure of the capillaries is held constant. It illustrates, at least in noninjured lungs, that at low lung volumes (as may occur with atelectasis), extra-alveolar vessels become narrow, and smooth muscle and elastic fibers in these collapsed vessels increase PVR. At high lung volumes, as alveolar volumes are increased and walls are thinned, capillaries are stretched, reducing their caliber and also increasing PVR (adapted from John West's Essential Physiology, 8th edition, Philadelphia: Lippincott & Williams, with permission) (141).