ALDA-1 treatment and prevention of pulmonary disease

Methods of treating or preventing allergic or pulmonary diseases characterized by endothelial dysfunction with Alda-1 are presented. Treatment of pulmonary endothelial cells subjected to hyperoxia with Alda-1 showed an increase in ALDH2 activity and expression. Treatment with Alda-1 also illustrated a decrease in oxidative stress, a decrease in reactive oxygen species (ROS), a decrease in apoptosis, a decrease in inflammation and an enhancement of mitochondrial membrane potential

ALDA-1 treatment and prevention of pulmonary disease

Methods of treating or preventing allergic or pulmonary diseases characterized by endothelial dysfunction with Alda-1 are presented. Treatment of pulmonary endothelial cells subjected to hyperoxia with Alda-1 showed an increase in ALDH2 activity and expression. Treatment with Alda-1 also illustrated a decrease in oxidative stress, a decrease in reactive oxygen species (ROS), a decrease in apoptosis, a decrease in inflammation and an enhancement of mitochondrial membrane potential

ALDA-1 treatment and prevention of pulmonary disease

Methods of treating or preventing allergic or pulmonary diseases characterized by endothelial dysfunction with Alda-1 are presented. Treatment of pulmonary endothelial cells subjected to hyperoxia with Alda-1 showed an increase in ALDH2 activity and expression. Treatment with Alda-1 also illustrated a decrease in oxidative stress, a decrease in reactive oxygen species (ROS), a decrease in apoptosis, a decrease in inflammation and an enhancement of mitochondrial membrane potential

4-Hydroxynonenal Regulates Mitochondrial Function in Human Small Airway Epithelial Cells

Prolonged exposure to oxidative stress causes Acute Lung Injury (ALI) and significantly impairs pulmonary function. Previously we have demonstrated that mitochondrial dysfunction is a key pathological factor in hyperoxic ALI. While it is known that hyperoxia induces the production of stable, but toxic 4-hydroxynonenal (4-HNE) molecule, it is unknown how the reactive aldehyde disrupts mitochondrial function. Our previous in vivo study indicated that exposure to hyperoxia significantly increases 4-HNE-Protein adducts, as well as levels of MDA in total lung homogenates. Based on the in vivo studies, we explored the effects of 4-HNE in human small airway epithelial cells (SAECs). Human SAECs treated with 25 μM of 4-HNE showed a significant decrease in cellular viability and increased caspase-3 activity. Moreover, 4-HNE treated SAECs showed impaired mitochondrial function and energy production indicated by reduced ATP levels, mitochondrial membrane potential, and aconitase activity. This was followed by a significant decrease in mitochondrial oxygen consumption and depletion of the reserve capacity. The direct effect of 4-HNE on the mitochondrial respiratory chain was confirmed using Rotenone. Furthermore, SAECs treated with 25 μM 4-HNE showed a time-dependent depletion of total Thioredoxin (Trx) proteins and Trx activity. Taken together, our results indicate that 4-HNE induces cellular and mitochondrial dysfunction in human SAECs, leading to an impaired endogenous antioxidant response

4-Hydroxynonenal Regulates Mitochondrial Function in Human Small Airway Epithelial Cells

Prolonged exposure to oxidative stress causes Acute Lung Injury (ALI) and significantly impairs pulmonary function. Previously we have demonstrated that mitochondrial dysfunction is a key pathological factor in hyperoxic ALI. While it is known that hyperoxia induces the production of stable, but toxic 4-hydroxynonenal (4-HNE) molecule, it is unknown how the reactive aldehyde disrupts mitochondrial function. Our previous in vivo study indicated that exposure to hyperoxia significantly increases 4-HNE-Protein adducts, as well as levels of MDA in total lung homogenates. Based on the in vivo studies, we explored the effects of 4-HNE in human small airway epithelial cells (SAECs). Human SAECs treated with 25 μM of 4-HNE showed a significant decrease in cellular viability and increased caspase-3 activity. Moreover, 4-HNE treated SAECs showed impaired mitochondrial function and energy production indicated by reduced ATP levels, mitochondrial membrane potential, and aconitase activity. This was followed by a significant decrease in mitochondrial oxygen consumption and depletion of the reserve capacity. The direct effect of 4-HNE on the mitochondrial respiratory chain was confirmed using Rotenone. Furthermore, SAECs treated with 25 μM 4-HNE showed a time-dependent depletion of total Thioredoxin (Trx) proteins and Trx activity. Taken together, our results indicate that 4-HNE induces cellular and mitochondrial dysfunction in human SAECs, leading to an impaired endogenous antioxidant response

The Cd/Zn Axis: Emerging Concepts in Cellular Fate and Cytotoxicity

Cadmium (Cd) is a toxic and carcinogenic substance that is present in the natural environment. The underlying biomolecular mechanisms of Cd toxicity are not completely understood, and it continues to be a significant research target due to its impact on public health. The primary routes of exposure are through ingestion of contaminated food and water and inhalation. Cd’s long biological half-life of 10–30 years allows it to accumulate in the body, leading to organ dysfunction notably in the kidney, liver, bone, and lungs. Cd has similar biochemical characteristics to Zinc (Zn). It shares the import transporters, ZIP8 and ZIP14, to enter the cells. This competitive behavior can be observed in multiple instances throughout the progression of Cd toxicity. Future studies on the biochemical interactions of Cd and Zn will elucidate the potential protective effects of Zn supplementation in reducing the effects of Cd toxicity. In addition, research can be focused on discovering key proteins and effective pathways for Cd elimination that confer fewer adverse effects than current antioxidant therapies

Deletion of P2X7 Attenuates Hyperoxia-induced Acute Lung Injury via Inflammasome Suppression

Increasing evidence shows that hyperoxia is a serious complication of oxygen therapy in acutely ill patients that causes excessive production of free radicals leading to hyperoxia-induced acute lung injury (HALI). Our previous studies have shown that P2X7 receptor activation is required for inflammasome activation during HALI. However, the role of P2X7 in HALI is unclear. The main aim of this study was to determine the effect of P2X7 receptor gene deletion on HALI. Wild-type (WT) and P2X7 knockout (P2X7 KO) mice were exposed to 100% O2 for 72 h. P2X7 KO mice treated with hyperoxia had enhanced survival in 100% O2 compared with the WT mice. Hyperoxia-induced recruitment of inflammatory cells and elevation of IL-1β, TNF-α, monocyte chemoattractant protein-1, and IL-6 levels were attenuated in P2X7 KO mice. P2X7 deletion decreased lung edema and alveolar protein content, which are associated with enhanced alveolar fluid clearance. In addition, activation of the inflammasome was suppressed in P2X7-deficient alveolar macrophages and was associated with suppression of IL-1β release. Furthermore, P2X7-deficient alveolar macrophage in type II alveolar epithelial cells (AECs) coculture model abolished protein permeability across mouse type II AEC monolayers. Deletion of P2X7 does not lead to a decrease in epithelial sodium channel expression in cocultures of alveolar macrophages and type II AECs. Taken together, these findings show that deletion of P2X7 is a protective factor and therapeutic target for the amelioration of hyperoxia-induced lung injury

Inflammasome Inhibition Suppresses Alveolar Cell Permeability Through Retention of Neuregulin-1 (NRG-1)

Background: Neuregulin (NRG)-1-human epidermal receptor (HER)-2 signaling pathway is a key regulator of IL-1β-mediated pulmonary inflammation and epithelial permeability. The inflammasome is a newly discovered molecular platform required for caspase-1 activation and maturation of IL-1β. However, the role of the inflammasome in NRG-1-HER2 signaling-mediated alveolar cell permeability is unknown. Methods: The inflammasome was activated or inhibited in THP-1 cells; supernatants from these cells were added to A549 cells and human small airway epithelial cells (HSAEC). The protein expression of NRG-1 and phospho-HER2 (pHER2) were measured by Western blot analysis and epithelial permeability was measured using Lucifer yellow dye. Results: Results reveal that alveolar permeability in A549 cells and HSAEC is increased when treated with supernatants of inflammasome-activated THP-1 cells. Alveolar permeability is significantly suppressed when treated with supernatant of inflammasome-inhibited THP-1 cells. Inflammasome-mediated permeability is decreased when A549 cells and HSAEC are pretreated with IL-1β receptor antagonist (IL-1βRA). In addition, HER2 kinase inhibitor AG825 or NRG-1 inhibitor TAPI inhibits inflammasome-mediated permeability in A549 cells and HSAEC demonstrating critical roles of IL-1β, NRG-1, and HER2 in inflammasome-mediated alveolar permeability. Conclusion: These findings suggest that inflammasome-induced alveolar cell permeability is mediated by NRG-1/HER2 signaling through IL-1β regulation

SOCS-1 rescues IL-1β-mediated suppression of epithelial sodium channel in mouse lung epithelial cells via ASK-1

Background: Acute lung injury (ALI) is characterized by alveolar damage, increased levels of pro-inflammatory cytokines and impaired alveolar fluid clearance. Recently, we showed that the deletion of Apoptosis signal-regulating kinase 1 (ASK1) protects against hyperoxia-induced acute lung injury (HALI) by suppressing IL-1β and TNF-α. Previously, our data revealed that the suppressor of cytokine signaling-1 (SOCS-1) overexpression restores alveolar fluid clearance in HALI by inhibiting ASK-1 and suppressing IL-1β levels. Furthermore, IL-1β is known to inhibit the expression of epithelial sodium channel α-subunit (ENaC) via a p38 MAPK signaling pathway. Objective: To determine whether SOCS-1 overexpression in MLE-12 cells would protect against IL-1β-mediated depletion of αENaC by suppressing ASK-1 expression. Methods: We co-transfected MLE-12 cells with SOCS-1 overexpressing plasmid with or without IL-1β in the presence or absence of sodium channel inhibitor, amiloride. We measured potential difference, transepithelial current, resistance, and sodium uptake levels across MLE-12 cells. We studied the effect of ASK-1 depletion, as well as ASK-1 and SOCS-1 overexpression on αENaC expression. Results: SOCS-1 overexpression sufficiently restored transepithelial current and resistance in MLE-12 cells treated with either IL-1β or amiloride. The αENaC mRNA levels and sodium transport were increased in SOCS-1 overexpressing MLE-12 cells exposed to IL-1β. Depletion of ASK-1 in MLE-12 cells increased αENaC mRNA levels. Interestingly, SOCS-1 overexpression restored αENaC expression in MLE-12 cells in the presence of ASK-1 overexpression. Conclusion: Collectively, these findings suggest that SOCS-1 may exert its protective effect by rescuing αENaC expression via suppression of ASK-1