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.

Keywords: alveolar epithelium; alveolar type II cells; emphysema; lung; oxidative stress; tissue homeostasis.

Figure 1

Multiple dysregulated signaling pathways in the pathogenesis of emphysema. Oxidative stress is the major contributor to emphysema. Reactive oxygen species (ROS) and related species disturb cell signaling and impair cell functions, while the antioxidant defense system is overwhelmed. These components are dynamically and progressively interactive over time, and their alterations can lead to emphysema development.