**12. Developmental abnormalities and PH**

[109-111]. In one study of 212 patients with ILD screened by echocardiography and/or right heart catheter 29 (14%) had PH and 13 (6%) had severe PH defined as PAP ≥ 35mmHg [112]. To clinically diagnose PH in ILD is a challenge due to the overlap of symptoms of breathless‐

The pathophysiology of PH due to chronic lung fibrosis is under active investigation (Figure 2). Mechanisms other than alveolar hypoxemia and loss of parenchymal tissue may lead to development of PH in this condition [113-115]. The development of pulmonary fibrosis was closely linked in experimental studies to elevated pulmonary artery pressures [116]. Vascular remodelling in ILDs is heterogeneous with fibrotic areas being less vascularised and normal tissue being hyper-vascularised with the creation of anastomoses between capillaries and pulmonary veins [108]. An imbalance has been observed between pro-angiogenic and antiangiogeneic factors with reduction of vascular endothelial growth factor (VEGF) and upregulation of epithelium-derived growth factor (EDGF). In animal models, reduction in VEGF has been linked to endothelial apoptosis and PH [108,117]. Vascular smooth muscle cell growth factors are thought to be released from apoptotic endothelial cells which in turn lead to muscularization of the vasculature which augments PH [116,117]. In addition, endothelial dysfunction with reduced levels nitric oxide and prostacyclins and increased presence of vasoconstrictive mediators, such as endothelin-1 and thromboxanes may contribute to the

Recent experimental work focused on the role of adenosine in development of PH in chronic lung disease [118]. Adenosine through G protein linked pathways has been associated with progression of fibrotic lung disease and PH through the adenosine receptor, A2bR [118,119]. Karmouty-Quintana et al. were able to demonstrate that inhibition of the A2bR, by inhibition or genetic removal of the receptor, slowed the progression of the fibrotic process and associated

Vascular remodelling has been observed in other forms of interstitial lung diseases. In systemic sclerosis an autoimmune disorder involving skin fibrosis, respiratory complications are the commonest causes of death [121]. The prevalence of PH in systemic sclerosis is as high as 45% [115]. Autoantibodies, including anti-fibrillin and anti-EC antibodies, have been implicated in endothelial apoptosis and endothelial injury with the resultant inflammatory reaction. Advanced systemic sclerosis is associated with reduced capillary density which could

In sarcoid, granulomatous involvement of the pulmonary arteries with occlusion and peri‐ vascular inflammation, invasion of pulmonary veins with inflammatory cells, and direct compression of the arteries by lymph nodes are thought to contribute to the development of PH. Endothelin-1 has an important role in PH in sarcoid with high levels reported in the broncho-alveolar fluid of affected patients [124]. Currently there is no clear evidence to suggest

Few small studies have suggested a possible role of vasodilators in attenuating the progression of PH in ILD [126,127]. The development of PH in ILD is associated with high mortality, hazard ratio for death of 8.5 (95%CI: 4-17) [128]. However, most guidelines do not recommend use of

a role for angiogenesis or endothelial injury in sarcoid-related PH [107,125].

PAH-specific treatments in patients with ILD [2,129].

ness and functional impairment in both conditions.

development of PH [108,116,117].

PH in rodents [120].

32 Pulmonary Hypertension

contribute to PH [108,122,123].

In the largest registry to date, 42 (12%) of 362 children (< 18 years) with confirmed PH (defined as mean PAP of ≥25mmHg) had associated respiratory diseases or hypoxemia [130]. Bronchopul‐ monary dysplasia (BPD) was the commonest condition; other disorders included congenital diaphragmatic hernia, congenital pulmonary hypoplasia and kyphoscoliosis [130]. BPD traditionally was defined by the presence of persistent respiratory distress, abnormal chest radiographyandrequirementforoxygensupplementation[131].Withimprovementsinneonatal care, persistent lung disease after prematurity is no longer characterised by florid fibro-prolifer‐ ative lung disease, but reduced vascular development and enlargement of distal airspaces associated with impaired gas exchange and development of PH [132]. Congenital diaphragmat‐ ic hernia presents similarly and is associated with variable lung growth leading to persistent PH [133]. Specific drug treatments for PH in this group of disorders have not been studied.
