Daily Ards Research Analysis

We previously identified a small molecule, UM101, predicted to bind to the substrate-binding groove of p38α mitogen-activated protein kinase (MAPK) near the binding site of its proinflammatory substrate, mitogen-activated protein kinase-activated protein kinase (MK)2. UM101 exhibited anti-inflammatory, endothelial-stabilizing, and lung-protective effects. To overcome its limited aqueous solubility and p38α binding affinity, we designed an analog of UM101, GEn-1124, with improved aqueous solubility, stability, and p38α-binding affinity. Compared with UM101, GEn-1124 has 18-fold greater p38α-binding affinity as measured by surface plasmon resonance, 11-fold greater aqueous solubility, enhanced barrier-stabilizing activity in thrombin-stimulated human pulmonary artery endothelial cells in vitro, and greater lung protection in vivo. GEn-1124 improved survival from 10%-40% in murine acute lung injury induced by combined exposure to intratracheal bacterial endotoxin lipopolysaccharide instillation and febrile-range hyperthermia and from 0% to 50% in a mouse influenza pneumonia model. Gene expression analysis by RNASeq in tumor necrosis factor α-treated human pulmonary artery endothelial cells showed that the gene-modifying effects of GEn-1124 were much more restricted to tumor necrosis factor α-inducible genes than those of the catalytic site p38 inhibitor, SB203580. Gene expression pathway analysis, confocal immunofluorescence analysis of p38α and MK2 subcellular trafficking, and surface plasmon resonance analysis of phosphorylated p38α:MK2 binding affinity supports a novel mechanism of action. GEn-1124 destabilizes the activated p38α:MK2 complex and dissociates nuclear export of MK2 and p38α, thereby promoting intranuclear retention and enhanced intranuclear signaling by phosphorylated p38α and accelerated inactivation of p38-free cytosolic MK2 by unopposed phosphatases. SIGNIFICANCE STATEMENT: We describe a novel analog of our first-in-class small molecule modulator of p38α/MK2 signaling targeted to a pocket near the glutamate-aspartate-containing substrate binding domain of p38α, which destabilizes the p38α:MK2 complex without blocking p38 catalytic activity or ablating downstream signaling. The result is a rebalancing of downstream proinflammatory and anti-inflammatory signaling, yielding anti-inflammatory, endothelial-stabilizing, and lung-protective effects with therapeutic potential in acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS), often preceded by acute lung injury (ALI), is characterized by the accumulation of inflammatory fluid in the lung alveoli, leaky alveolar epithelium and endothelium, and overexpression of proinflammatory cytokines. This progression from ALI to ARDS is a major contributor to the high mortality observed in patients with COVID-19. The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to lung angiotensin-converting enzyme 2 (ACE2), and in addition to facilitating viral cell entry, it plays an important role in the development of ALI and ARDS, especially in the later phases of COVID-19 as well as long-COVID. Protein tyrosine phosphatase (PTP) 4A3 is a key mediator of ARDS pathology. This study tested the hypothesis that targeting PTP4A3 would prevent COVID-19-associated ALI. Intratracheal administration of SARS-CoV-2 spike protein subunit 1 to K18-hACE2 transgenic mice expressing human ACE2 elicited pulmonary and systemic inflammation, leaky alveoli, overexpression of cytokines, structural lung injury, and lung dysfunction; all these symptoms were ameliorated by the selective, allosteric inhibitor of PTP4A3, KVX-053. These findings provide the first evidence supporting a role for PTP4A3 in the development of SARS-CoV-2-mediated ALI. SIGNIFICANCE STATEMENT: This study tested the hypothesis that targeting PTP4A3 would prevent COVID-19-associated ALI/ARDS. Intratracheal administration of SARS-CoV-2 spike protein subunit 1 to K18-hACE2 transgenic mice expressing human ACE2 elicited pulmonary and systemic inflammation, leaky alveoli, overexpression of cytokines and chemokines, structural lung injury, and lung dysfunction; all these symptoms were ameliorated by the selective, allosteric inhibitor of PTP4A3, KVX-053. These findings suggest that this novel PTP4A3 inhibitor may be useful against COVID-19 and potentially other viral-induced ARDS.

Background: The evidence of sex disparity in acute respiratory distress syndrome (ARDS) is scarce and varies widely. Objective: This observational, retrospective study aimed to determine the effect of sex on the sepsis-related ARDS and other short outcomes in critically ill patients with sepsis. Methods: A total of 2,111 adult patients with sepsis who were admitted to three central intensive care units (ICUs) of Wuhan Tongji Hospital between 2012 and 2022 were included in our analysis. Sex was considered as an exposure factor, with sepsis-related ARDS as the primary outcome, and in-hospital mortality, invasive mechanical ventilation support, septic shock, and other complications as secondary outcomes. Results: Among the 2,111 enrolled patients, 1,287 were males (61%) and 824 were females (39%). The incidence of sepsis-related ARDS was higher in males compared to females ( P = 0.001), as well as in-hospital mortality ( P = 0.009). Multivariate logistic analysis demonstrated that male sex remained independently associated with an increased risk of sepsis-related ARDS (adjusted odds ratio [aOR] = 1. 493 [1.034-2.156], P = 0.032). Propensity score matching analysis also indicated that males had 58% higher odds of developing sepsis-related ARDS (aOR = 1.584 [1.022-2.456], P = 0.040). Regarding secondary outcomes, male sex was identified as a risk factor for in-hospital mortality (aOR = 1.536 [1.087-2.169], P = 0.015) and invasive mechanical ventilation support (aOR = 1.313 [1.029-1.674], P = 0.028) in the fully adjusted model. Sensitivity analysis that included postmenopausal females and age-matched male counterparts showed that male sex still remained to be a risk factor of developing sepsis-related ARDS (aOR = 1.968 [1.241-3.120], P = 0.004). Conclusions: Male sex was identified as an independent risk factor for sepsis-related ARDS and in-hospital mortality among critically ill patients with sepsis. Given the retrospective design of this study, the relationship between sex and sepsis-related ARDS requires further validation through large-scale randomized controlled trials in the future.