Abstract
Mediators of inflammation, oxidative stress, and chemoattractants drive the hypoxemic mechanisms that accompany pulmonary fibrosis. Patients with idiopathic pulmonary fibrosis commonly have obstructive sleep apnea, which potentiates the hypoxic stimuli for oxidative stress, culminating in systemic inflammation and generalized vascular endothelial damage. Comorbidities like pulmonary hypertension, obesity, gastroesophageal reflux disease, and hypoxic pulmonary vasoconstriction contribute to chronic hypoxemia leading to the release of proinflammatory cytokines that may propagate clinical deterioration and alter the pulmonary fibrotic pathway. Tissue inhibitor of metalloproteinase (TIMP-1), interleukin- (IL-) 1α, cytokine-induced neutrophil chemoattractant (CINC-1, CINC-2α/β), lipopolysaccharide induced CXC chemokine (LIX), monokine induced by gamma interferon (MIG-1), macrophage inflammatory protein- (MIP-) 1α, MIP-3α, and nuclear factor- (NF-) κB appear to mediate disease progression. Adipocytes may induce hypoxia inducible factor (HIF) 1α production; GERD is associated with increased levels of lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and tumor necrosis factor alpha (TNF-α); pulmonary artery myocytes often exhibit increased cytosolic free Ca2+. Protein kinase C (PKC) mediated upregulation of TNF-α and IL-1β also occurs in the pulmonary arteries. Increased understanding of the inflammatory mechanisms driving hypoxemia in pulmonary fibrosis and obstructive sleep apnea may potentiate the identification of appropriate therapeutic targets for developing effective therapies.
Highlights
Pulmonary fibrosis results from an exaggerated and persistent deposition of extracellular matrix within the lung parenchyma with severe consequences on respiratory function
Various inflammatory cytokines play key roles in progression of Pulmonary hypertension (PH); these include tissue inhibitor of metalloproteinase (TIMP1), cytokine-induced neutrophil chemoattractant (CINC-1, CINC-2α/β), interleukin- (IL-) 1α, monokine induced by gamma interferon (MIG-1), lipopolysaccharide induced CXC chemokine (LIX), macrophage inflammatory protein- (MIP-) 1α, MIP-3α, and nuclear factor- (NF-) κB [20]
Pulmonary arterial expression of TNF-α and IL-1β has been demonstrated under hypoxic conditions and the observed upregulation of these cytokines is dependent on the activation of protein kinase C (PKC) [28]
Summary
Pulmonary fibrosis results from an exaggerated and persistent deposition of extracellular matrix within the lung parenchyma with severe consequences on respiratory function. While the underlying etiology in many cases remains idiopathic or attributed to infective causes, it is believed that a significant proportion is attributable to the presence of chronic comorbid conditions frequently observed in fibrotic lung diseases [17] (Figure 1). Often, these chronic conditions which are present in patients with OSA contribute to the amplification of hypoxemia by the release of chemoattractants, hormones, and specific inflammatory mediators which alter the fibrotic pathway within the pulmonary parenchyma. Pulmonary arterial expression of TNF-α and IL-1β has been demonstrated under hypoxic conditions and the observed upregulation of these cytokines is dependent on the activation of protein kinase C (PKC) [28]
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