The Plant Hormone Indole-3-Acetic Acid Helps the Endothelial Barrier Seal after Lung Injury

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) can be induced by a sudden inflammatory burst, causing loss of the endothelial–epithelial barrier integrity; pulmonary edema; extensive cell death; and, ultimately, lung architectural damage (1, 2). Pulmonary endothelial cells play a central role, controlling chemotaxis, maintaining the endothelial barrier while regulating permeability of cell junctions for leukocytes to reach sites of infection, and maintaining vascular tone for adequate perfusion and gas exchange (1, 2). Despite advances in clinical management, ALI/ARDS continues to be associated with high morbidity and mortality. A better understanding of the cellular mechanisms alongside the development of novel therapeutics is a critical need. In this issue of the Journal, Shaheen and colleagues (pp. 307–317) address the possibility of using indole-3-acetic acid (IAA) as a therapy for ALI/ARDS conditions, with a focus on pulmonary endothelial cell biology and endothelial barrier permeability (3).

IAA, an abundant plant hormone, reportedly has antioxidant and antiinflammatory properties (3). It has been detected in multiple human body compartments and may derive from the enteric flora in mammals (4, 5). Its effect seems to be dose-dependent in various organ systems, with recent disparate controversial outcomes related to cardiovascular physiology (6). IAA’s mechanism of action is not known; however, because of its purported beneficial effects, Shaheen and colleagues investigated the potential of IAA as a pretreatment for ALI/ARDS. Through a series of elegant and well-designed experiments, the researchers found IAA pretreatment decreases of proinflammatory cytokine secretion and improvement of transendothelial electrical resistance, a measure of endothelial barrier function. These results were supported by experiments in a murine model of ALI/ARDS in which IAA pretreatment decreased pulmonary edema, measured using a lung wet-to-dry ratio, and extravasation assays. The authors report that the dose-dependent effects of IAA decrease endothelial barrier disruption and increase endothelial integrity.

Regulation of lung endothelial cell barrier integrity is complex, with the organization and contraction of cytoskeletal elements being a critical and tightly orchestrated process. Heat Shock Protein 90 (HSP90) is a proinflammatory chaperone protein involved in numerous pathologic processes but chiefly studied in cancer migration, metastases, and blood–barrier disruption (7). HSP90 activation leads to endothelial cell contraction with a net effect of increasing endothelial barrier permeability. This seems to hold true in the pulmonary endothelium, where HSP90 activation in models of ALI/ARDS is associated with pulmonary edema and disruption of endothelial barrier integrity. In fact. HSP90 inhibitors are a focus of current studies testing their potential to hasten the resolution of inflammatory states that can lead to ALI/ARDS (8). Using sophisticated knockout murine models and vector-induced models of ubiquitin-specific peptidase 40 (USP40) expression inhibition, Shaheen and colleagues demonstrate a mechanism of action for IAA to induce USP40, which increased the deubiquitination of the HSP90β isomer.

Collectively, the studies by Shaheen and colleagues provide convincing evidence that IAA pretreatment leads to decreased acute inflammatory pulmonary responses through the activation and stabilization of USP40. This ultimately reduces the action of HSP90β and promotes the maintenance of endothelial barrier integrity, with decreased lung injury (Figure 1). Although immune histopathologic correlation would have provided additional strong validation, the findings reinforce the importance of a gut–lung axis in which commensal bacteria indirectly affect the health of the lung by conferring inflammatory protection through IAA, a gut bacterial byproduct (9). This further highlights a mechanism for the role of microbiotic gut dysregulation in human lung diseases.

Although the pretreatment protocols used in this work are ideal for assessing prophylactic therapy in numerous conditions, this is not necessarily directly applicable in a clinical setting, as it is not feasible yet to predict which patients will develop severe complications such as ARDS. Thus, future studies with IAA as “a rescue after exposure” are needed to consider it for human use, a limitation that is acknowledged by the authors (3). Caution is also warranted because increased endothelial barrier permeability is a physiologic mechanism that contributes to immune responses that facilitate the clearance of pathogens from the lung tissue. If IAA leads to the inhibition of immune responses, it is possible that immune dysregulation can lead to ineffective pathogen elimination in cases of bacterial pneumonias.

Models of adult ALI/ARDS commonly utilize murine laboratory animals with fully developed alveoli. It would be beneficial to see the potential protective effects of IAA on the preterm lung, which is commonly exposed to inflammatory states. Preterm lungs are characterized by a capillary network that undergoes multiple transitions (progenitor to differentiated states), and are further characterized by having immature endothelial cell barrier integrity, especially at the canalicular and saccular stages of development (10, 11). Newborn murine animal models are phenotypically similar to premature stages of human lung development, although the animals are able to survive without the assistance of ventilatory support (12). Chronic ventilatory support associated with hyperoxic and hypoxic exposures that cause oxidative stress and inflammatory conditions such as chorioamnionitis are implicated in the development of chronic lung disease of prematurity that exhibit alveolar developmental arrest and vascular maldevelopment (13). Pulmonary edema caused by an immature and dysregulated endothelial barrier is a complication of these sequelae of preterm birth. Although chronic diuretic therapies are a mainstay (14), it is intriguing to consider whether IAA treatment could affect endothelial cell integrity in the context of established vascular dysfunction. Additionally, respiratory distress syndrome of the newborn is pathophysiologically distinct from adult ARDS (1, 2, 15). The effects of IAA on such a system are unknown, but further studies such as the ones conducted by Shaheen and colleagues could be revealing.