Hypoxia and Local Inflammation in Pulmonary Artery Structure and Function

Abstract

Hypoxia is recognized as a contributor to pulmonary vascular diseases such as pulmonary hypertension. Hypoxia-induced inflammatory changes can enhance structural and functional changes in pulmonary artery (PA) in the context of PH. Accordingly, understanding how hypoxia and inflammation are linked in the context of pulmonary artery structure and function could be relevant towards development of novel therapies for PH. In this regard, factors such as thymic stromal lymphopoietin (TSLP), an inflammatory cytokine, and brain-derived neurotrophic factor (BDNF), a neurotrophin, have been found critical for nonvascular systems such as airway and asthma. While TSLP canonically affects the immune system, in nonvascular systems, noncanonical effects such as altered [Ca] and cell proliferation have been noted: aspects also relevant to the PA, where there is currently little to no data. Similarly, better known in the nervous system, there is increasing evidence that BDNF is locally produced by structural cells of the airway and can contribute to asthma pathophysiology. In this chapter, we summarize the potential relevance of factors such as TSLP and BDNF to the PA and in the context of hypoxia influences towards development of PH. We focus on cell sources and targets such as PA endothelial cells (PAECs) and smooth muscle cells (PASMCs), and the effects of TSLP or BDNF on intracellular Ca responses to vasoconstrictor agonist, cell proliferation, and potential signaling cascades involved.

Bullous pemphigoid: The role of type 2 inflammation in its pathogenesis and the prospect of targeted therapy

“…For example, in the lung, type 2 alveolar cells are a primary source of TSLP and IL-33 in the lung ( 23 ), whereas in the small intestine and skin, tuft cells and keratinocytes are a major source of IL-25, respectively ( 24 , 25 ). In addition, other non-epithelial cells can also produce alarmins, with airway smooth muscle cells secreting TSLP ( 26 ) and fibroblasts producing IL-33 ( 27 ). Under the effect of these alarmins, tissue-resident ILC2s are activated and increase the production of cytokines of IL-4, IL-5, IL-9 and IL-13 ( 28 ), termed type 2 cytokines.…”

Smouldering fire or conflagration? An illustrated update on the concept of inflammation in pulmonary arterial hypertension

“…In addition, the mere hypoxic state that is associated with so many respiratory and cardiovascular diseases leads to inflammatory responses by itself: at altitude, for example, hypoxia increases the levels of circulating interleukin (IL)-6 and C-reactive protein, even in healthy humans [9]. Hypoxia induces inflammation within the pulmonary artery through local expression of pro-contractile and proliferative growth factors and pro-inflammatory mediators like vascular endothelial growth factor, brain-derived neurotrophic factor or thymic stromal lymphopoietin that are generated in resident cells of the vessel wall [10]. Moreover, hypoxia induces the auto-oxidation of haemoglobin within red blood cells, and thereby increases superoxide production: higher amounts of H 2 O 2 are spilled into the pulmonary circulation, and oxidative stress at the level of microvascular endothelial cells triggers the activation of the NF-κB pathway and local recruitment of leukocytes (figure 5) [11].…”

17β-Estradiol Promotes Apoptosis in Airway Smooth Muscle Cells Through CD38/SIRT1/p53 Pathway

“…Hypoxia is recognized as a critical contributor to pulmonary diseases including asthma, airway obstruction and pulmonary hypertension (1–3). Hypoxia stimulates airway inflammation and remodeling, and subsequently induces apoptosis in airway smooth muscle cells (ASMCs) during airway remodeling (4).…”