Post-Translational Changes in BPD: Insights into Pathogenesis and Therapies

Abstract

BPD is a significant respiratory disorder among premature infants and significantly impacts pulmonary function and their long-term health. Although great strides have been made in neonatal care, effective therapeutic strategies are still in short supply, as the complex molecular mechanisms that underlie the pathogenesis of BPD continue to pose an enormous challenge. Besides genetic factors, PTMs have recently emerged as important regulators of cellular functions, thereby providing another layer of complexity to the disease process. Different PTMs, among which are phosphorylation, acetylation, ubiquitination, SUMOylation, methylation, glycosylation, glycation, S-glutathionylation, and S-nitrosylation, affect signal transduction pathways that have roles in lung inflammation, oxidative stress, and worsened alveolar development. In this review, the complex nature of the role of PTMs in BPD is discussed, focusing on their role in disease progression and as therapeutic interventions. A deeper understanding of these molecular modifications could pave the way for innovative treatment strategies to mitigate BPD's long-term consequences and improve outcomes in affected neonates.

Introduction

Bronchopulmonary dysplasia is a chronic lung disorder that primarily affects preterm infants who are subjected to prolonged mechanical ventilation and a prolonged course of oxygen therapy. It involves interrupted alveolar and vascular development and produces long-term respiratory complications. Advances in neonatal care did improve the survival rate, but BPD remains the first cause of morbidity among preterm infants, thus indicating an immediate need for effective therapeutic interventions.

Recent studies have shown that post-translational modifications (PTMs) of proteins are one of the pivotal regulatory mechanisms in the pathogenesis of BPD. Such chemical modifications affect protein function, stability, and interactions at a cellular level to influence inflammation, oxidative stress, apoptosis, and tissue remodeling. Understanding the specific roles of PTMs may hold new promise for developing targeted therapeutic strategies.

Pathophysiology of Bronchopulmonary Dysplasia

BPD is a multifactorial disease influenced by prenatal, perinatal, and postnatal factors, including:

• Premature Birth: Immature lung development predisposes neonates to respiratory distress syndrome (RDS), necessitating mechanical ventilation and supplemental oxygen.

• Inflammation: Persistent inflammatory responses contribute to alveolar simplification and fibrosis.

• Oxidative Stress: High oxygen exposure and mechanical ventilation trigger the generation of reactive oxygen species (ROS), leading to cellular damage.

• Impaired Angiogenesis: Disrupted vascular endothelial growth factor (VEGF) signaling results in abnormal pulmonary microvasculature.

• Growth Factor Dysregulation: Dysregulation of fibroblast growth factors (FGFs) and transforming growth factor-beta (TGF-β) impairs lung repair and regeneration.

Given the complexity of BPD pathogenesis, post-translational modifications play an essential role in modulating these pathways.

Key Post-Translational Modifications in BPD

1. Phosphorylation

Phosphorylation is a reversible modification involving the addition of a phosphate group to proteins, regulating signaling pathways essential for lung development. In BPD, abnormal phosphorylation of key signaling proteins such as mitogen-activated protein kinases (MAPKs) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) exacerbates inflammation and oxidative stress, promoting lung injury.

2. Acetylation

Histone and non-histone protein acetylation modulates gene expression and cellular responses. In BPD, dysregulation of histone acetyltransferases (HATs) and histone deacetylases (HDACs) alters chromatin structure, leading to excessive pro-inflammatory cytokine production and impaired lung repair mechanisms.

3. Ubiquitination

Ubiquitination targets proteins for degradation via the ubiquitin-proteasome system. Altered ubiquitination of lung-protective proteins, such as surfactant proteins, disrupts pulmonary homeostasis and aggravates alveolar damage. Moreover, excessive ubiquitination of anti-inflammatory mediators contributes to sustained inflammation in BPD.

4. SUMOylation

Small ubiquitin-like modifier (SUMO) modification regulates protein stability and stress responses. Aberrant SUMOylation of transcription factors involved in lung development, such as hypoxia-inducible factor-1 alpha (HIF-1α), impairs cellular adaptation to oxidative stress, exacerbating lung injury.

5. Methylation

Protein and DNA methylation play vital roles in epigenetic regulation of gene expression. Hypomethylation of pro-inflammatory genes and hypermethylation of lung-protective genes have been observed in BPD, contributing to sustained inflammation and impaired alveolarization.

6. Glycosylation and Glycation

Glycosylation is essential for protein folding and stability, while glycation (non-enzymatic glycosylation) results in protein dysfunction. Aberrant glycosylation of pulmonary surfactant proteins disrupts their function, impairing lung compliance. Additionally, advanced glycation end-products (AGEs) accumulate in BPD, exacerbating oxidative stress and inflammation.

7. S-Glutathionylation

S-glutathionylation protects proteins from oxidative damage by modifying cysteine residues. In BPD, oxidative stress leads to excessive glutathionylation of essential lung proteins, disrupting their function and impairing cellular defense mechanisms.

8. S-Nitrosylation

S-nitrosylation modulates protein activity through nitric oxide (NO) signaling. Dysregulated S-nitrosylation in BPD affects endothelial nitric oxide synthase (eNOS), impairing vascular development and leading to pulmonary hypertension.

Therapeutic Implications of PTMs in BPD

Given the significant role of PTMs in BPD pathogenesis, targeting these modifications offers a promising therapeutic approach. Potential strategies include:

1. Kinase and Phosphatase Modulators:

   • Inhibitors of MAPKs and NF-κB phosphorylation to reduce inflammation.

   • Activation of phosphatases that counteract pathological phosphorylation events.

2. Epigenetic Modulators:

   • HDAC inhibitors balance histone acetylation and mitigate inflammatory gene expression.

   • DNA methylation modulators to restore lung-protective gene expression.

3. Proteasome and SUMOylation Inhibitors:

   • Targeted inhibition of excessive ubiquitination to preserve lung-protective proteins.

   • SUMOylation regulators to enhance cellular stress responses.

4. Antioxidant and Glycation Inhibitors:

   • Use of glycation inhibitors to prevent AGE accumulation and oxidative stress.

   • Antioxidants targeting glutathionylation pathways to restore protein function.

5. Nitric Oxide Modulation:

   • Enhancing S-nitrosylation balance to promote endothelial function and lung vascularization.

Future Directions and Research Perspectives

While PTM-targeted therapies hold promise for BPD treatment, further research is needed to:

• Identify Specific PTM Targets: Characterizing PTM profiles in BPD patients to determine potential therapeutic biomarkers.

• Develop Selective Modulators: Designing small molecules or biologics that specifically modulate PTMs involved in BPD pathogenesis.

• Conduct Clinical Trials: Translating preclinical findings into effective therapies through rigorous clinical trials in preterm infants.

Conclusion

Bronchopulmonary dysplasia remains among the most daunting challenges within neonatal medicine, owing to comparatively few therapeutic options and sequelae with long-term respiratory consequences. Post-translational modifications are critical to the regulation of key signaling pathways implicated in BPD pathogenesis. Understanding those modifications not only provides deeper insights into disease mechanisms but also opens up avenues for targeted therapeutic strategies. Leverage advances in molecular medicine may suggest new ways PTM-targeted therapies may offer novel solutions in improving lung health in premature infants affected by BPD.

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