Temporal Dynamics of Oxidative Stress and Inflammation in Bronchopulmonary Dysplasia

Abstract

Bronchopulmonary dysplasia (BPD) is the most common lung complication of prematurity. Despite extensive research, our understanding of its pathophysiology remains limited, as reflected by the stable prevalence of BPD. Prematurity is the primary risk factor for BPD, with oxidative stress (OS) and inflammation playing significant roles and being closely linked to premature birth. Understanding the interplay and temporal relationship between OS and inflammation is crucial for developing new treatments for BPD. Animal studies suggest that OS and inflammation can exacerbate each other. Clinical trials focusing solely on antioxidants or anti-inflammatory therapies have been unsuccessful. In contrast, vitamin A and caffeine, with antioxidant and anti-inflammatory properties, have shown some efficacy, reducing BPD by about 10%. However, more than one-third of very preterm infants still suffer from BPD. New therapeutic agents are needed. A novel tripeptide, N-acetyl-lysyltyrosylcysteine amide (KYC), is a reversible myeloperoxidase inhibitor and a systems pharmacology agent. It reduces BPD severity by inhibiting MPO, enhancing antioxidative proteins, and alleviating endoplasmic reticulum stress and cellular senescence in a hyperoxia rat model. KYC represents a promising new approach to BPD treatment.

Keywords: anti-inflammatory; antioxidant; bronchopulmonary dysplasia; endoplasmic reticulum stress; inflammation; oxidative stress; senescence; temporal relationship; therapeutic intervention.

Figure 1

The interaction between oxidative stress (OS) and inflammation in general pathologies. Infection and autoimmune diseases are the most common prototypes that activate macrophages and neutrophils. The reactive oxygen species (ROS) generated by myeloperoxidase (MPO), NADPH oxidase, and uncoupled electron transport chain represent inflammation preceding OS. Metabolic disorders (diabetes mellitus and hyperlipidemia) or neurodegenerative diseases (Parkinson’s disease and Alzheimer’s disease) have mitochondrial dysfunction with increased OS, which then results in secondary inflammation. However, OS and inflammation frequently form a vicious cycle and reciprocally elicit each other. →: from upstream to downstream; +: positive effect.

Figure 2

The contributing role of OS and inflammation in developing bronchopulmonary dysplasia (BPD). Increased OS and inflammation are seen antenatally for preterm birth. The surfactant deficiency after preterm birth results in respiratory distress, and antioxidant deficiency leads to sensitivity to OS-induced injury. Postnatal oxygen support, mechanical ventilation, and infection further aggravate OS and inflammation in the premature lung that culminates into BPD. Nutritional deprivation, which weakens the regenerative process, also contributes to BPD. DAMP: damage-associated molecular pattern; IUGR: intrauterine growth restriction; PIH: pregnancy-induced hypertension (pre-eclampsia, eclampsia, and chronic hypertension); PROM: premature rupture of the membranes; ROS: reactive oxygen species. Solid blue arrow: direct relationship; Dashed blue arrow: distant relationship; Broken blue arrow: positive reinforcement.

Figure 3

The BPD destructive cycle. The destructive cycle is constructed according to the results of the rat BPD model. OS from hyperoxia or inflammation caused by lipopolysaccharide (LPS) causes myeloid cell infiltration. Myeloperoxidase (MPO) released by macrophages and neutrophils will generate hypochlorous acid (HOCl) from the surrounding chloride anion and H₂O₂ released by activated myeloid cells. As one of the most potent free radicals, HOCl can kill or injure nearby cells by releasing high mobility group box 1 (HMGB1), eliciting endoplasmic reticulum (ER) stress, apoptosis, and cellular senescence. HMGB1 is the most potent DAMP, which binds to Toll-like receptor 4 (TLR4) or the receptor for advanced glycation end product (RAGE). ER stress can generate ROS to regain its ability to fold protein and glycosylate nascent proteins. ER stress will activate sterile inflammation and promote cellular senescence. The senescence-associate secretory phenotype (SASP) can lead to chronic inflammation by releasing pro-inflammatory cytokines (IL6, TNFα, HMGB1). The hypermetabolic state of senescent cells and proliferation arrest of the stem/progenitor cells contribute to impaired alveolar formation. These changes form a complex interaction network and self-perpetuate the destructive cycle. The figure is reproduced from [50] under the Creative Commons CC BY 4.0 license). Solid red and purple arrows: direct relationship; Arrowhead: direction of the destructive cycle.