Pulmonary Hypertension (PH) associated with Idiopathic Pulmonary Fibrosis

Chronic lung diseases including the idiopathic pulmonary fibrosis (IPF) represent the third leading cause of death in the US.
Despite reductions in mortality in cardiovascular diseases and cancer, the mortality rates for lung diseases have remained
unaffected over the last decades. One of the major complications of chronic lung injury and strongly linked to mortality is the
presence of pulmonary hypertension (PH).

PH is defined as a mean pulmonary arterial pressure (mPAP) of >25mmHg. The pathological process o f PH development is
characterized by an extensive vascular remodeling including an enhanced proliferation of pulmonary artery smooth muscles cells.
This leads to narrowing and obliteration of the vessel lumen resulting in an increase of the vascular tone. PH is divided into five
comprehensive subsets of PH. According to the World Health Organization (WHO), IPF-induced PH is part of the Group III
(associated with chronic lung diseases affecting lung parenchyma and hypoxemia).

IPF is a progressive, debilitating and fatal lung disease that affects approximately 3 million people worldwide. IPF is characterized by
inflammation and fibrosis of the lungs, hindering the ability to process oxygen and causing shortness of breath. Mortality from
IPF is increasing steadily worldwide with a median survival time from diagnosis of 2-5 years. It is estimated that there will be
between 28,000 and 65,000 deaths in Europe and between 13,000 and 17,000 deaths in the United States from IPF per year.

The prevalence of PH amongst IPF patients is dependent upon the severity of IPF. We estimate the incidence to be between
10-50% of IPF patients who are affected by PH.

A direct consequence of the development of PH is its direct impact of right ventricle (RV) failure. In IPF, fibrosis and loss of
lung parenchyma contribute to PH and RV hypertrophy by obliterating pulmonary vascular beds.

Bleomycin as a model of IPF and PH

An important difficulty in studying the development of PH in IPF is the lack of animal models that exhibit both lung fibrosis and PH.
The most common model of lung fibrosis uses the exposure of rodents to the bleomycin (BLM). BLM is a glycopeptide antibiotic
commonly used as an anticancer agent. It is widely used in research for its induction of pulmonary fibrosis in animals, which is
functionally and histologically similar to fibrotic lung disease in humans. The progression of fibrosis may lead to respiratory failure,
yielding a poor prognosis in patients with various types of interstitial lung disorders. In this model, BLM is intratracheally
instilled leading to the development of fibrosis by day 14, and reaching a steady state by day 21.

Pulmonary hypertension related to pulmonary fibrosis occurs when the scarred tissue affects the pulmonary arteries by
compressing the vessels. The scar tissue increases resistance to blood flow from the heart to the lungs, leading to increased high
pressure in the pulmonary arteries and the right heart ventricle.

The mechanism of action behind this physiopathology involved many mediators and steps. Epithelial cells 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 endothelial
cells (EC) 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 produce 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 enhance production of vascular SMC (VSMC) growth factors, which is important for remodeling of mesenchymal cells in the PA wall. However, EC apoptosis also results in proliferation of apoptosis–resistant ECs or endothelial progenitors, with the consequence 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.