Dysregulated Cell Signaling in Pulmonary Emphysema

Abstract

Pulmonary emphysema is characterized by the destruction of alveolar septa and irreversible airflow limitation. Cigarette smoking is the primary cause of this disease development. It induces oxidative stress and disturbs lung physiology and tissue homeostasis. Alveolar type II (ATII) cells have stem cell potential and can repair the denuded epithelium after injury; however, their dysfunction is evident in emphysema. There is no effective treatment available for this disease. Challenges in this field involve the large complexity of lung pathophysiological processes and gaps in our knowledge on the mechanisms of emphysema progression. It implicates dysregulation of various signaling pathways, including aberrant inflammatory and oxidative responses, defective antioxidant defense system, surfactant dysfunction, altered proteostasis, disrupted circadian rhythms, mitochondrial damage, increased cell senescence, apoptosis, and abnormal proliferation and differentiation. Also, genetic predispositions are involved in this disease development. Here, we comprehensively review studies regarding dysregulated cell signaling, especially in ATII cells, and their contribution to alveolar wall destruction in emphysema. Relevant preclinical and clinical interventions are also described.

Impaired Alveolar Re-Epithelialization in Pulmonary Emphysema

“…Increasing evidence shows multiple dysregulated signaling pathways in ATII cells in emphysema [25,28,46], contributing to apoptosis/proliferation imbalance and alveolar destruction. Besides, less responsive mesenchymal cells [8] and dysfunctional endothelium [63] were observed in patients.…”

“…Furthermore, characteristics of cellular senescence were observed in emphysema patients [46]. Treatments targeting cellular senescence have beneficial effects on animal models of emphysema.…”

“…Oxidative stress and high inflammation trigger a series of dysregulated signaling pathways and cell dysfunction, leading to loss of cell homeostasis and alveolar destruction in emphysema [46]. Alveolar epithelial cell apoptosis/proliferation imbalance was reported in patients with this disease [47].…”

The effects of lipoic acid on respiratory diseases

“…Moreover, alpha-1 antitrypsin deficiency, which is a rare genetic risk factor, may induce early disease occurrence [215] . The pathogenesis of pulmonary emphysema involves the dysregulation of various signalling pathways, including oxidative stress, defective antioxidant defence systems, inflammatory responses, and cell dysfunction [216] . A study showed that treatment with 100 µM LA could scavenge hypochlorous acid in vitro [217] , impairing hypochlorous acid-mediated inactivation of alpha-1-antiproteinase and elastase and reducing the damage associated with lung emphysema .…”