Effects of hypercapnia on the lung

Abstract

Gases are sensed by lung cells and can activate specific intracellular signalling pathways, and thus have physiological and pathophysiological effects. Carbon dioxide (CO₂ ), a primary product of oxidative metabolism, can be sensed by eukaryotic cells eliciting specific responses via recently identified signalling pathways. However, the physiological and pathophysiological effects of high CO₂ (hypercapnia) on the lungs and specific lung cells, which are the primary site of CO₂ elimination, are incompletely understood. In this review, we provide a physiological and mechanistic perspective on the effects of hypercapnia on the lungs and discuss the recent understanding of CO₂ modulation of the alveolar epithelial function (lung oedema clearance), epithelial cell repair, innate immunity and airway function.

Keywords: airway function; alveolar epithelial function; carbon dioxide; hypercapnia; injury and repair; innate immunity and host defense.

Figure 1. Hypercapnia impairs alveolar fluid reabsorption

Reduction of lung edema clearance is associated with the endocytosis of the Na⁺,K⁺‐ATPase from the plasma membrane of alveolar epithelial cells, which leads to decreased Na⁺,K⁺‐ATPase activity. During hypercapnia protein kinase C (PKC)‐ζ directly phosphorylates the Na⁺,K⁺‐ATPase α1‐subunit at Ser 18 residue, leading to endocytosis of the Na⁺,K⁺‐ATPase. The activation of PKC‐ζ is regulated by AMP kinase (AMPK) via Ca²⁺/calmodulin‐dependent protein kinase kinase‐β (CAMKK‐β) and extracellular signal‐regulated kinase (ERK). The endocytosis of the Na⁺,K⁺‐ATPase by hypercapnia is also regulated by c‐Jun‐N‐Terminal Kinase (JNK) via an AMPK‐PKC‐ζ signaling. JNK promotes the phosphorylation of LMO7b, which regulates the actin cytoskeleton in epithelial cells, followed by its colocalization and interaction with the Na⁺,K⁺‐ATPase and several components of the clathrin‐dependent endocytic machinery. The protein kinase A (PKA)‐Iα also plays a role in the Na⁺,K⁺‐ATPase endocytosis during hypercapnia. Namely, hypercapnia via a CO₂/HCO₃ ⁻‐sensitive soluble adenylyl cyclase (sAC) increases the production of cAMP, activates PKA‐Iα and in turn, the phosphorylation of the actin cytoskeleton component α‐adducin, culminating in the Na⁺,K⁺‐ATPase endocytosis from the cell plasma membrane.

Figure 2. Hypercapnia inhibits alveolar epithelial repair

Hypercapnia inhibits proliferation of alveolar epithelial cells due to mitochondrial dysfunction resulting from hypercapnia‐induced miR‐183 which down‐regulates the TCA cycle enzyme isocitrate dehydrogenase‐2 (IDH2). Hypercapnic acidosis impairs alveolar epithelial cell migration by the NF‐κB‐dependent mechanism.

Figure 3. Hypercapnia suppresses innate immunity and host defence

A, hypercapnia selectively inhibits mRNA and protein expressions of IL‐6 and TNF and decreases phagocytosis in macrophages. B, hypercapnia inhibits autophagy in macrophages by increasing expressions of Bcl‐2 and Bcl‐xL which bind Beclin 1. C, hypercapnia inhibits activation of the canonical NF‐κB pathway that drives expression of inflammatory cytokine genes while promoting activation of the non‐canonical NF‐κB pathway.