**11. PH in interstitial lung diseases**

Interstitial lung diseases (ILD) are characterized by restrictive lung physiology with progres‐ sive impairment of gas exchange resulting in alveolar hypoxemia and PH. Mortality in these conditions is predicted by the degree of hypoxemia, spirometry and functional capacity as defined by 6MWD and presence of PH [105-108].

The prevalence of PH in IPF is high and varies between 32 - 85%. PH is mostly of moderate severity although in a few patients pulmonary pressures may approximate systemic levels [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‐ ness and functional impairment in both conditions.

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 development of PH [108,116,117].

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 PH in rodents [120].

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 contribute to PH [108,122,123].

**12. Developmental abnormalities and PH**

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

of the vessel; *Farkas L et al., AJRCMB 2011 [107], Reprinted with permission of the American Thoracic Society.*

**Figure 2.** Concept for the development of pulmonary hypertension (PH) in IPF/UIP. Epithelial injury with subsequent production of different mediators is the hallmark of fibrosis induction. These mediators induce fibroblast activation with extracellular matrix (ECM) deposition, which leads to fibrosis. Some of these mediators (e.g., TGF-β) also activate ECs and, as a result of a shift in favor of increased angiostatic (e.g., pigment epithelium–derived factor [PEDF]) and reduced angiogenic factors (e.g., vascular endothelial growth factor [VEGF]), EC apoptosis results. Apoptotic ECs pro‐ duce less vasodilators, but more vasoconstrictors, which leads to augmented vasoconstriction of smooth muscle cells (SMCs). At the same time, EC apoptosis gives rise to a reduction in vascular density, but also to enhanced production of vascular SMC (VSMC) growth factors, which is important for remodeling of mesenchymal cells in the PA wall. How‐ ever, EC apoptosis also results in proliferation of apoptosis-resistant ECs or endothelial progenitors, with the conse‐ quence of angioproliferative lesions, including plexiform lesions. Another component of PA wall remodeling is the release of additional factors generated in the fibrotic tissue, which contribute to PA wall remodeling from the outside

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[133]. Specific drug treatments for PH in this group of disorders have not been studied.

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

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

**Figure 2.** Concept for the development of pulmonary hypertension (PH) in IPF/UIP. Epithelial injury with subsequent production of different mediators is the hallmark of fibrosis induction. These mediators induce fibroblast activation with extracellular matrix (ECM) deposition, which leads to fibrosis. Some of these mediators (e.g., TGF-β) also activate ECs and, as a result of a shift in favor of increased angiostatic (e.g., pigment epithelium–derived factor [PEDF]) and reduced angiogenic factors (e.g., vascular endothelial growth factor [VEGF]), EC apoptosis results. Apoptotic ECs pro‐ duce less vasodilators, but more vasoconstrictors, which leads to augmented vasoconstriction of smooth muscle cells (SMCs). At the same time, EC apoptosis gives rise to a reduction in vascular density, but also to enhanced production of vascular SMC (VSMC) growth factors, which is important for remodeling of mesenchymal cells in the PA wall. How‐ ever, EC apoptosis also results in proliferation of apoptosis-resistant ECs or endothelial progenitors, with the conse‐ quence of angioproliferative lesions, including plexiform lesions. Another component of PA wall remodeling is the release of additional factors generated in the fibrotic tissue, which contribute to PA wall remodeling from the outside of the vessel; *Farkas L et al., AJRCMB 2011 [107], Reprinted with permission of the American Thoracic Society.*
