Pulmonary arterial hypertension (PAH) is a relatively rare, chronic disease of the pulmonary vasculature characterized by increased extracellular matrix deposition, increased pulmonary infiltrates, and accumulation of inflammatory cells within the PA wall causing increased pulmonary vascular resistance. Such characteristics can manifest into the clinical symptom of syncope, chest pain, and fatigue. Elevated pulmonary arterial pressure and increased pulmonary vascular resistance can progress rapidly and ultimately lead to right heart failure and death. PAH is classified into the following categories: (i) idiopathic PAH, (ii) heritable PAH (HPAH), (iii) drug- and toxin-induced PAH, (iv) associated PAH (APAH), and (v) persistent PAH of the newborn (PPHN). Although it is believed that inflammation is central to the progression of PAH, the precise mechanism isn't clear. What's more, the increased recruitment of monocytes and macrophages into the perivascular space is a prominent feature of PAH.
There are two kinds of macrophages in the lung: alveolar and interstitial macrophages. Many evidence has been performed that after birth, embryonic lung macrophages from the yolk sac differentiate into interstitial macrophages. These macrophages exist in the pulmonary interstitium and are considered antigen-presenting cells that interact with interstitial T lymphocytes to trigger adaptive immune responses. And further experiments have indicated that alveolar macrophages are from embryonic liver mononuclear cells rather than the yolk sac. Some evidence has indicated that alveolar macrophages can self-divide without being replaced by stable circulating monocytes. Peroxisome proliferator-activated receptor (PPAR)-γ expression on fetal liver monocytes is vital for the progression of alveolar macrophages. The alveolar macrophages are mainly related to local immune homeostasis and a vital component of the series of cells that protect the lungs from viral infections.
Fig.1 The potential roles of the macrophages in PAH. (Chen, 2020)
Pulmonary vascular lesions in PAH patients exist in a highly inflamed microenvironment. Variable cytokines, growth factors, and oxygen levels affect the recruitment, activation, and polarization of macrophages in pulmonary hypertension. Vascular Remodeling is driven by inflammation in PAH. Polarized macrophages can produce a different panel of cytokines and chemokines such as collagen type I, express α-smooth muscle actin, resistin, thrombospondin-1, Legumain, chemokine receptor 2 (CCR2) /CCR5, to facilitate endothelial injury, increase the synthesis of extracellular matrix (ECM) proteins, and the apoptosis-resistant proliferation of pulmonary artery smooth muscle cells. All these facts promote continuous vasoconstriction and vascular remodeling. Interventions targeting macrophages have confirmed their function in pulmonary vascular remodeling and PAH. Apoptosis of vascular cells stimulates anti-inflammatory M2 macrophages, which release proliferative factors for damage resolution and activate vascular remodeling. On the contrary, necrotic damage of vascular cells stimulates M1 macrophages with pro-inflammatory properties increasing perivascular inflammation, vascular permeability, and fibrosis. Many experiments indicated the shift of macrophages from M2 to M1 protected mice against PAH.
Fig.2 Macrophages and vascular remodeling in the PAH. (Rafikova, 2019)
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