The major task of the respiratory tract is the exchange between inhaled atmospheric oxygen and carbon dioxide carried by the bloodstream, which is ensured by a thin but large surface area formed by type I and type II alveolar epithelial cells. Both the upper and the lower respiratory epithelia are lined by a thin (0.2 µM) aqueous layer (1), referred to as airway surface liquid (ASL) and alveolar lining fluid (AFL), respectively. This fluidic component serves—in concerted action with surfactant, mucus, and ciliary beat—to reduce alveolar surface tension and prevent atelectasis as well as to defend against invading pathogens. To maintain the composition of the ASL and AFL and to prevent alveolar flooding, lung fluid homeostasis is tightly controlled by the expression and activity of ion channels and pumps. These channels and pumps establish an osmotic gradient between airspace and interstitium, driving paracellular or aquaporin- (AQP3, 4, and 5) (2) mediated fluid movement across the respiratory epithelium. Among these, the apical amiloride-sensitive epithelial sodium channel (ENaC) and the amiloride-insensitive cyclic nucleotide-gated cation channel (CNG) acting together with the basolaterally located Na,K-ATPase (NKA) promote transcellular sodium transport (3), which is accompanied in the alveolar epithelium by chloride uptake from the apical cystic fibrosis membrane conductance regulator (CFTR) (4). However, in the airway, CFTR promotes chloride secretion to regulate mucus density (5). In addition, Ca²⁺-activated ion channels (CaCC) promote apical chloride secretion, further supported by basolateral chloride uptake via Na⁺/K⁺/2Cl⁻ cotransporters (NKCC) (6) as well as potassium ion channels such as Kv7.1, contributing to cellular membrane potential and buildup of an electrochemical gradient necessary for apical chloride secretion (7). Additional factors influencing fluid homeostasis are epithelial (im)permeability established by tight junction proteins as well as endothelial integrity limiting the extravasation of fluid from the blood vessels driven by changes in the capillary hydrostatic pressure (8, 9).

Pulmonary infections commonly disturb ion and thus fluid homeostasis, resulting in abnormal changes of ASL, AFL, and alveolar edema formation. Both viral and bacterial pathogens are common causative agents for acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS), which are characterized by a widespread inflammation within the lungs, extensive flooding of the alveolar airspace with protein-rich exudate fluid and impaired gas exchange leading to respiratory failure and resulting in mortality rates of 40–58% (10, 11). Additionally, sepsis resulting from primary infections at other sites is often complicated by the development of severe lung injury during the onset of bacteremia, resulting in lung failure and accounting for as many as half of all cases of ARDS (12). Although some of the pathogen-derived effects on ion transport during lung injury have been reported to be caused directly by the pathogen–host cell interaction (13), accumulating evidence suggests that auto- and paracrine mediators of local and/or systemic inflammatory responses mounted upon pathogen recognition and replication induce—among other pathophysiological changes—impaired ion transport and alveolar fluid clearance (AFC), resulting in edema formation and persistence. Importantly, mortality in ARDS patients has repeatedly been found to correlate with persistence of alveolar edema (11, 14).

In this review, we will highlight advances in the understanding of how inflammatory responses in pulmonary infection affect ion transport, including common patterns and unique pathways activated by different respiratory pathogens, and how these mechanisms might be modulated to improve the outcomes of ARDS patients.

There are numerous reports showing that pulmonary infection leads to loss of barrier integrity and edema accumulation as well as the role of distinct mediators on impairing ion channel or transporter function on the alveolar, bronchial, and gut epithelia. However, there have been few studies showing how infectious agents modulate soluble signaling molecules that affect ion and fluid homeostasis. Several reports from the last decade have reestablished an important role for soluble, inflammatory mediators in the progression of ARDS. For example, Lee et al. demonstrated that exposure of human ATII cells to pulmonary edema fluid derived from ARDS patients alone was sufficient to downregulate the ion channels and pumps involved in AFC, including ENaC, the NKA, and CFTR (15). Concomitantly, it was established that viral or bacterial lung infections lead to edema accumulation and impair clearance via the induction of paracrine factors. For example, influenza A virus (IAV) has been shown to increase apical potassium secretion by upregulation of the apical potassium channel KCNN4 by a paracrine signaling event, thus disturbing the osmotic gradient necessary for edema clearance (16). Similarly, Pseudomonas aeruginosa evokes a strong inflammatory response and lung edema accumulation related with the modulation of ENaC subunit expression (17, 18). In the next paragraphs, we will provide an overview on interconnections of mediators released in pulmonary infection and their effects on ion and fluid homeostasis (Figure 1).

To add to the complexity of airway and alveolar fluid regulation, it has been suggested that not only ion channels, pumps, and transporters are modulated by signaling factors released upon pulmonary infection but also changes in ion transport influence the respiratory inflammatory response. For example, the transporter NKCC1—which plays a critical role in basolateral ion transport—can affect the severity of pneumonia and sepsis and consequently severity of lung injury, by regulating the ability of the alveolar–capillary barrier to modulate neutrophil infiltration into the air spaces of the lung (80). Lack of NKCC1 in a mouse model of pneumonia infection with K. pneumonia or LPS resulted in increased numbers of neutrophils in the lavage fluid, decreased bacteremia, and importantly mortality. It has, therefore, been suggested that the activity of NKCC1 contributes to edema formation and decreased neutrophil migration into the lung air spaces, probably contributing to reduce bacterial killing and the subsequent development of severe sepsis (81–83). Similarly, mutations of CFTR can amplify lung inflammation by upregulating pro-inflammatory responses caused by an increase in cytokine production upon NFκB activation in lung epithelial cells (84). Lack of functional neutrophilic CFTR in a model of LPS-induced lung inflammation contributes to inflammatory imbalance with NFκB translocation and a reduction of anti-inflammatory cytokines such as IL-10, favoring the increase in lung vascular permeability (85). Also ion imbalances in response to expression of viral ion channels or viroporins, has been recognized as potential pathogen recognition pathway that favors inflammasome activation and the release of IL-1β, TNF, and IL-6, which might contribute to the limitation of virus spreading (86, 87).

As stated above, pulmonary infections—especially in severe cases—can lead to lung edema accumulation and impaired edema clearance. Lung edema results in impaired oxygenation and organ dysfunction which if not resolved leads to high mortality of patients with ARDS (11, 14). Current treatment options for infection-induced ARDS include antivirals and antibiotics. However, there is increased antibiotic resistance—reported for pathogens such as K. pneumoniae, Escherichia coli, Staphylococcus aureus and P. aeruginosa (82, 83, 88)—or lack of readily available treatment options for some acute emerging agents such as zoonotic influenza viruses or middle east respiratory syndrome coronavirus (89–91). Current approaches to treat ARDS patients include low tidal volume mechanical ventilation, positive end expiratory pressure, fluid management, and extracorporeal membrane oxygenation as measures to primarily improve oxygenation (92). Interestingly, lung-protective ventilation strategies have not only been reported to reduce mortality by 22% in patients with ARDS but also to diminish the number of neutrophils and the concentration of pro-inflammatory cytokines released in patient lavage fluids.

Novel approaches targeting host mediators known to promote lung edema formation and impair clearance such as studies on TIP peptide [see Tumor Necrosis Factor Alpha (TNF-α) above] administration in ARDS are being studied. Initial reports showed that AP301, a synthetic peptide mimicking TIP, induces ENaC activity in type II alveolar epithelial cells from dogs, pigs, and rats (93) and improves lung function in a porcine lung injury model (94). A subsequent phase II clinical trial with AP301 in ventilated ARDS patients resulted in improved AFC and oxygenation of these patients (95). Also, mesenchymal stem cells, which have been reported to improve epithelial barrier integrity in human AEC II treated with a cytokine mix composed of a combination of IL-1β, TNFα, and IFNγ (96), are currently tested for safety and efficacy in phase II trials (clinical trial identifiers NCT02097641, NCT01775774, NCT02112500). Studies on β2-agonists, which had been previously shown to improve vectorial sodium transport and edema clearance (97, 98), did not improve ARDS outcomes (99, 100), possibly due to an enhanced inflammatory response driven by lung macrophages (101). Further treatment options targeting para- or autocrine signaling events affecting AFC in preclinical models include glucocorticoids that suppress inflammation and upregulate both NKA (102) and ENaC (103, 104), neutralizing antibodies directed against virus-specific release of macrophage TRAIL that improve NKA expression as well as AFC in IAV-infected mice (24) and nitric oxide synthase inhibitors aminoguanidine or N(omega)-monomethyl-l-arginine (l-NMMA) that protect against pulmonary edema in LPS-induced lung injury as well as in IAV infection (77, 105).

Pathogen-induced lung injury but also sepsis can lead to widespread respiratory inflammation that favors accumulation of lung edema leading to multiorgan dysfunction and poor outcomes. Recent advances in the development of novel treatment strategies targeting respiratory ion homeostasis show encouraging results, identifying them as promising candidates to improve AFC in ALI which could potentially improve the survival of patients with ARDS.

CP, SH, JS, and EL have performed bibliographic research and drafted the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.