Chloride channels in the lung: Challenges and perspectives for viral infections, pulmonary arterial hypertension, and cystic fibrosis.

Fine control over chloride homeostasis in the lung is required to maintain membrane excitability, transepithelial transport as well as intra- and extracellular ion and water homeostasis. Over the last decades, a growing number of chloride channels and transporters have been identified in the cells of the pulmonary vasculature and the respiratory tract. The importance of these proteins is underpinned by the fact that impairment of their physiological function is associated with functional dysregulation, structural remodeling, or hereditary diseases of the lung. This paper reviews the field of chloride channels and transporters in the lung and discusses chloride channels in disease processes such as viral infections including SARS-CoV- 2, pulmonary arterial hypertension, cystic fibrosis and asthma. Although chloride channels have become a hot research topic in recent years, remarkably few of them have been targeted by pharmacological agents. As such, we complement the putative pathophysiological role of chloride channels here with a summary of their therapeutic potential.

Potassium Channels in the Transition from Fetal to the Neonatal Pulmonary Circulation.

The transition from the fetal to the neonatal circulation includes dilatation of the pulmonary arteries (PA) and closure of the Ductus Arteriosus Botalli (DAB). The resting membrane potential and various potassium channel activities in smooth muscle cells (SMC) from fetal and neonatal PA and DAB obtained from the same species has not been systematically analyzed. The key issue addressed in this paper is how the resting membrane potential and the whole-cell potassium current (IK) change when PASMC or DABSMC are transitioned from hypoxia, reflecting the fetal state, to normoxia, reflecting the post-partal state. Patch-clamp measurements were employed to characterize whole-cell K+ channel activity in fetal and post-partal (newborn) PASMC and DABSMC. The main finding of this paper is that the SMC from both tissues use a similar set of K+ channels (voltage-dependent (Kv), calcium-sensitive (KCa), TASK-1 and probably also TASK-2 channels); however, their activity level depends on the cell type and the oxygen level. Furthermore, we provide the first evidence for pH-sensitive non-inactivating K+ current in newborn DABSMC and PASMC, suggesting physiologically relevant TASK-1 and TASK-2 channel activity, the latter particularly in the Ductus Arteriosus Botalli.

Revisiting the Large-Conductance Calcium-Activated Potassium (BKCa) Channels in the Pulmonary Circulation.

Potassium ion concentrations, controlled by ion pumps and potassium channels, predominantly govern a cell's membrane potential and the tone in the vessels. Calcium-activated potassium channels respond to two different stimuli-changes in voltage and/or changes in intracellular free calcium. Large conductance calcium-activated potassium (BKCa) channels assemble from pore forming and various modulatory and auxiliary subunits. They are of vital significance due to their very high unitary conductance and hence their ability to rapidly cause extreme changes in the membrane potential. The pathophysiology of lung diseases in general and pulmonary hypertension, in particular, show the implication of either decreased expression and partial inactivation of BKCa channel and its subunits or mutations in the genes encoding different subunits of the channel. Signaling molecules, circulating humoral molecules, vasorelaxant agents, etc., have an influence on the open probability of the channel in pulmonary arterial vascular cells. BKCa channel is a possible therapeutic target, aimed to cause vasodilation in constricted or chronically stiffened vessels, as shown in various animal models. This review is a comprehensive collation of studies on BKCa channels in the pulmonary circulation under hypoxia (hypoxic pulmonary vasoconstriction; HPV), lung pathology, and fetal to neonatal transition, emphasising pharmacological interventions as viable therapeutic options.