**5. Pathobiologic basis of therapy**

The pathophysiology of IPAH is not fully elucidated An elevated pulmonary vascular resistance seems to result from an imbalance between locally produced vasodilators and vasoconstrictors, in addition to vascular wall remodeling.

Three major pathobiologic pathways (nitric oxide, endothelin, and prostacyclin) play impor‐ tant roles in the development and progression of PAH.

#### **5.1. Nitric Oxide (N.O)**

The endothelium-derived relaxing factor nitric oxide (NO), a potent pulmonary vasodilator, is produced in high levels in the upper and lower airways by nitric oxide synthase II (NOSII) and affects the pulmonary vascular tone in concert with the low NO levels that are produced by nitric oxide synthase III (NOSIII) in the vascular endothelium. NO causes smooth muscle relaxation and proliferation, maintaining the normal pulmonary vascular tone. Patients with IPAH have low levels of NO in their exhaled breath, and the severity of the disease inversely correlates with NO reaction products in bronchoalveolar lavage fluid. [18], [19]

Vascular endothelial cell factor (VEGF) promotes endothelial cell proliferation and is identical to the tumor factor responsible for inducing increased vascular permeability. Lung and brain express high levels of VEGF messenger RNA, and hypoxia triggers the production of VEGF. Furthermore, the presence of inflammatory cells in the perimeter of structurally altered vessels suggests that inflammatory cell-derived cytokines and growth factors may participate in the pathogenesis of PPH. Based on these results PPH may also represent a disorder of endothelial

Pulmonary Arterial Hypertension: An Overview

http://dx.doi.org/10.5772/56055

5

Blood thrombin activity is increased in patients with pulmonary hypertension, indicating activation of intravascular coagulation, whereas soluble thrombomodulin, a cell membrane protein that acts as an important site of thrombin binding and coagulation inactivation, is decreased. In addition, PGI2 and NO, both inhibitors of platelet aggregation, are decreased at the level of the injured endothelial cell. Circulating platelets in patients with PAH seem to be in a continuous state of activation and contribute to the prothrombotic milieu by aggregating

**•** Vasoactive intestinal peptide (VIP) (systemic vasodilator, decreases pulmonary artery pressure and pulmonary vascular resistance, inhibits platelet activation and vascular

**•** Vascular endothelial growth factor (VEGF) & receptors (participate in angiogenesis, appears

Early symptoms are nonspecific. The most common symptoms include dyspnea, weakness and recurrent syncope. Other symptoms include fatigue, angina, and abdominal distention.

The physical signs of pulmonary hypertension include left parasternal lift, loud pulmonary component of the second heart sound (P2), pansystolic murmur of tricuspid regurgitation, diastolic murmur of pulmonary insufficiency, and right ventricular S3. Jugular vein distention, hepatomegaly, peripheral edema, ascites, central cyanosis and cool extremities may be seen in

Symptoms at rest are reported only in very advanced cases.[1], [24]

Diagnostic approach is summarized in Figure 1.[25]

patients with advanced disease. [25] The lung examination is usually normal.

cell differentiation and growth. [23]

at the level of the injured endothelial cells.[3]

**5.6. Other Factors contributing to PAH**

smooth muscle cell proliferation)

to be disordered in PAH)

**6. Signs and symptoms**

**7. Investigations**

**5.5. Thrombosis**

#### **5.2. Endothelin-1**

Endothelin-1 is a peptide produced by the vascular endothelium that has potent vasoconstric‐ tive and proliferative paracrine actions on the vascular smooth muscle cells. The pulmonary circulation plays an important role in the production and clearance of endothelin-1, and this physiologic balance is reflected in the circulating levels of endothelin-1. Patients with pulmo‐ nary hypertension, IPAH in particular, have an increased expression of endothelin-1 in pulmonary vascular endothelial cells, and serum endothelin-1 levels are increased in patients with pulmonary hypertension.[20], [21]

#### **5.3. Prostacyclin**

The endothelium also produces prostacyclin (PGI2) by cyclooxygenase metabolism of arachidonic acid. Prostacyclin causes vasodilation throughout the human circulation and is an inhibitor of platelet aggregation by its action on platelet adenylate cyclase. The final enzyme in the production of PGI2 is prostacyclin synthase. The remodeled pulmonary vasculature in lung tissue obtained from patients with severe IPAH expresses lower levels of prostacyclin synthase when compared with normal lung tissue. [22]

### **5.4. Remodeling**

In IPAH, pulmonary vascular smooth muscle cells that normally have a low rate of multipli‐ cation undergo proliferation and hypertrophy. Those smooth cell changes arise from the loss of the antimitogenic endothelial substances (e.g., PGI2 and NO) and an increase in mitogenic substances (e.g., endothelin-1). Other stimuli arise from locally activated platelets, which release thromboxane A2 and serotonin; thromboxane A2 and serotonin act as growthpromoting substances on the vascular smooth muscle cells. Both are vasoconstrictors and serotonin also promotes smooth muscle cell hypertrophy and hyperplasia. In addition to the smooth muscle cell proliferation, abnormalities in extracellular matrix contribute to the medial hypertrophy in PAH.[3] These lead to intimal narrowing and increased resistance to blood flow.

An abnormal proliferation of endothelial cells occurs in the irreversible plexogenic lesion. The plexiform lesions in IPAH have been considered an abnormal growth of modified smooth muscle cells. These lesions are glomeruloid structures forming channels in branches of the pulmonary artery. These may result from a deregulated growth of endothelial cells. [23]

Because the plexiform lesions bear some resemblance to the neovascularization induced by malignant gliomas at both the morphological and immunohistochemical level, one might hypothesize that the plexogenic vessels also represent a unique form of active angiogenesis. Vascular endothelial cell factor (VEGF) promotes endothelial cell proliferation and is identical to the tumor factor responsible for inducing increased vascular permeability. Lung and brain express high levels of VEGF messenger RNA, and hypoxia triggers the production of VEGF. Furthermore, the presence of inflammatory cells in the perimeter of structurally altered vessels suggests that inflammatory cell-derived cytokines and growth factors may participate in the pathogenesis of PPH. Based on these results PPH may also represent a disorder of endothelial cell differentiation and growth. [23]

#### **5.5. Thrombosis**

and affects the pulmonary vascular tone in concert with the low NO levels that are produced by nitric oxide synthase III (NOSIII) in the vascular endothelium. NO causes smooth muscle relaxation and proliferation, maintaining the normal pulmonary vascular tone. Patients with IPAH have low levels of NO in their exhaled breath, and the severity of the disease inversely

Endothelin-1 is a peptide produced by the vascular endothelium that has potent vasoconstric‐ tive and proliferative paracrine actions on the vascular smooth muscle cells. The pulmonary circulation plays an important role in the production and clearance of endothelin-1, and this physiologic balance is reflected in the circulating levels of endothelin-1. Patients with pulmo‐ nary hypertension, IPAH in particular, have an increased expression of endothelin-1 in pulmonary vascular endothelial cells, and serum endothelin-1 levels are increased in patients

The endothelium also produces prostacyclin (PGI2) by cyclooxygenase metabolism of arachidonic acid. Prostacyclin causes vasodilation throughout the human circulation and is an inhibitor of platelet aggregation by its action on platelet adenylate cyclase. The final enzyme in the production of PGI2 is prostacyclin synthase. The remodeled pulmonary vasculature in lung tissue obtained from patients with severe IPAH expresses lower levels of prostacyclin

In IPAH, pulmonary vascular smooth muscle cells that normally have a low rate of multipli‐ cation undergo proliferation and hypertrophy. Those smooth cell changes arise from the loss of the antimitogenic endothelial substances (e.g., PGI2 and NO) and an increase in mitogenic substances (e.g., endothelin-1). Other stimuli arise from locally activated platelets, which release thromboxane A2 and serotonin; thromboxane A2 and serotonin act as growthpromoting substances on the vascular smooth muscle cells. Both are vasoconstrictors and serotonin also promotes smooth muscle cell hypertrophy and hyperplasia. In addition to the smooth muscle cell proliferation, abnormalities in extracellular matrix contribute to the medial hypertrophy in PAH.[3] These lead to intimal narrowing and increased resistance to blood

An abnormal proliferation of endothelial cells occurs in the irreversible plexogenic lesion. The plexiform lesions in IPAH have been considered an abnormal growth of modified smooth muscle cells. These lesions are glomeruloid structures forming channels in branches of the pulmonary artery. These may result from a deregulated growth of endothelial cells. [23]

Because the plexiform lesions bear some resemblance to the neovascularization induced by malignant gliomas at both the morphological and immunohistochemical level, one might hypothesize that the plexogenic vessels also represent a unique form of active angiogenesis.

correlates with NO reaction products in bronchoalveolar lavage fluid. [18], [19]

**5.2. Endothelin-1**

4 Pulmonary Hypertension

**5.3. Prostacyclin**

**5.4. Remodeling**

flow.

with pulmonary hypertension.[20], [21]

synthase when compared with normal lung tissue. [22]

Blood thrombin activity is increased in patients with pulmonary hypertension, indicating activation of intravascular coagulation, whereas soluble thrombomodulin, a cell membrane protein that acts as an important site of thrombin binding and coagulation inactivation, is decreased. In addition, PGI2 and NO, both inhibitors of platelet aggregation, are decreased at the level of the injured endothelial cell. Circulating platelets in patients with PAH seem to be in a continuous state of activation and contribute to the prothrombotic milieu by aggregating at the level of the injured endothelial cells.[3]

#### **5.6. Other Factors contributing to PAH**

