Defective autophagy impairs ATF3 activity and worsens lung injury during endotoxemia

Aguirre, Alina; López-Alonso, Inés; González-López, Adrián; Amado-Rodríguez, Laura; Batalla-Solís, Estefanía; Astudillo, Aurora; Blázquez-Prieto, Jorge; Fernández, Álvaro F.; Galván, José A.; Santos, Claudia C. dos; Albaiceta, Guillermo M.

doi:10.1007/s00109-014-1132-7

Cited by 44 publications

(35 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We first employed fasting, a well-accepted model to induce autophagy. Fasting and starvation induce a rapid and strong induction of autophagy in mice (38) and 24 h fasting induces autophagy in the lung and ameliorates lung inflammation (39). We also confirmed that our fasting protocol induced autophagy in the lung (Figure S4).…”

Section: Fasting Attenuates Hypoxemia In Lps/mv-induced Ali With Decrsupporting

confidence: 78%

See 1 more Smart Citation

Autophagy Protects Against Developing Increased Lung Permeability and Hypoxemia by Down Regulating Inflammasome Activity and IL-1β in LPS Plus Mechanical Ventilation-Induced Acute Lung Injury

et al. 2020

View full text Add to dashboard Cite

Targeting inflammasome activation to modulate interleukin (IL)-1β is a promising treatment strategy against acute respiratory distress syndrome and ventilator-induced lung injury (VILI). Autophagy is a key regulator of inflammasome activation in macrophages. Here, we investigated the role of autophagy in the development of acute lung injury (ALI) induced by lipopolysaccharide (LPS) and mechanical ventilation (MV). Two hours before starting MV, 0.2 mg/kg LPS was administered to mice intratracheally. Mice were then placed on high-volume MV (30 ml/kg with 3 cmH 2 O positive end-expiratory pressure for 2.5 h without additional oxygen application). Mice with myeloid-specific deletion of the autophagic protein ATG16L1 (Atg16l1 fl/fl LysM Cre ) suffered severe hypoxemia (adjusted p < 0.05) and increased lung permeability (p < 0.05, albumin level in bronchoalveolar lavage fluid) with significantly higher IL-1β release into alveolar space (p < 0.05). Induction of autophagy by fasting-induced starvation led to improved arterial oxygenation (adjusted p < 0.0001) and lung permeability (p < 0.05), as well as significantly suppressed IL-1β production (p < 0.01). Intratracheal treatment with anti-mouse IL-1β monoclonal antibody (mAb; 2.5 mg/kg) significantly improved arterial oxygenation (adjusted p < 0.01) as well as lung permeability (p < 0.05). On the other hand, deletion of IL-1α gene or use of anti-mouse IL-1α mAb (2.5 mg/kg) provided no significant protection, suggesting that the LPS and MV-induced ALI is primarily dependent on IL-1β, but independent of IL-1α. These observations suggest that autophagy has a protective role in controlling inflammasome activation and production of IL-1β, which plays a critical role in developing hypoxemia and increased lung permeability in LPS plus MV-induced acute lung injury.

show abstract

Section: Fasting Attenuates Hypoxemia In Lps/mv-induced Ali With Decrsupporting

confidence: 78%

“…WT C57BL/6J male mice were fasted for 20 h prior to MV with free-access water (38,39). Some mice were administered trehalose (1 g/kg, MP Biochemicals, Solon, OH, USA) intraperitoneally at the time point of 48, 24, and 2 h before starting MV.…”

Section: Fasting and Trehalose Treatmentmentioning

confidence: 99%

Autophagy Protects Against Developing Increased Lung Permeability and Hypoxemia by Down Regulating Inflammasome Activity and IL-1β in LPS Plus Mechanical Ventilation-Induced Acute Lung Injury

et al. 2020

View full text Add to dashboard Cite

show abstract

“…It should be noted that in a few studies LPS has been shown to induce autophagy in airway epithelial cells. 33,34 Currently it is not clear why such a difference in findings exists. One plausible explanation is that the induction of autophagy in lung disease pathogenesis is exactly cell type and pathogen dependent.…”

Section: Discussionmentioning

confidence: 99%

Activation of MTOR in pulmonary epithelium promotes LPS-induced acute lung injury

et al. 2016

View full text Add to dashboard Cite

MTOR (mechanistic target of rapamycin [serine/threonine kinase]) plays a crucial role in many major cellular processes including metabolism, proliferation and macroautophagy/autophagy induction, and is also implicated in a growing number of proliferative and metabolic diseases. Both MTOR and autophagy have been suggested to be involved in lung disorders, however, little is known about the role of MTOR and autophagy in pulmonary epithelium in the context of acute lung injury (ALI). In the present study, we observed that lipopolysaccharide (LPS) stimulation induced MTOR phosphorylation and decreased the expression of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 β)-II, a hallmark of autophagy, in mouse lung epithelium and in human bronchial epithelial (HBE) cells. The activation of MTOR in HBE cells was mediated by TLR4 (toll-like receptor 4) signaling. Genetic knockdown of MTOR or overexpression of autophagy-related proteins significantly attenuated, whereas inhibition of autophagy further augmented, LPS-induced expression of IL6 (interleukin 6) and IL8, through NFKB signaling in HBE cells. Mice with specific knockdown of Mtor in bronchial or alveolar epithelial cells exhibited significantly attenuated airway inflammation, barrier disruption, and lung edema, and displayed prolonged survival in response to LPS exposure. Taken together, our results demonstrate that activation of MTOR in the epithelium promotes LPS-induced ALI, likely through downregulation of autophagy and the subsequent activation of NFKB. Thus, inhibition of MTOR in pulmonary epithelial cells may represent a novel therapeutic strategy for preventing ALI induced by certain bacteria.

show abstract

“…Iron loading RAW cells increased the proportion of non-functional mitochondria relative to total mitochondria. Others have shown that damaged or non-functional mitochondria produce more mtROS 18, 35 . Mitochondrial mass can be increased by increasing mitochondrial biogenesis, decreasing mitophagy, or both.…”

Section: Discussionmentioning

confidence: 99%

Iron Loading Exaggerates the Inflammatory Response to the Toll-like Receptor 4 Ligand Lipopolysaccharide by Altering Mitochondrial Homeostasis

et al. 2017

View full text Add to dashboard Cite

Background Perioperative and critically ill patients are often exposed to iron (in the form of parenteral-iron administration or blood transfusion) and inflammatory stimuli, but the effects of iron loading on the inflammatory response are unclear. Recent data suggest that mitochondrial reactive oxygen species have an important role in the innate immune response and that increased mitochondrial reactive oxygen species production is a result of dysfunctional mitochondria. We tested the hypothesis that increased intracellular iron potentiates lipopolysaccharide-induced inflammation by increasing mitochondrial reactive oxygen species levels. Methods Murine macrophage cells were incubated with iron and then stimulated with lipopolysaccharide. C57BL/6 wild-type mice were intraperitoneally injected with iron and then with lipopolysaccharide. Markers of inflammation and mitochondrial superoxide production were examined. Mitochondrial homeostasis (the balance between mitochondrial biogenesis and destruction) was assessed, as were mitochondrial mass and the proportion of nonfunctional to total mitochondria. Results Iron loading of mice and cells potentiated the inflammatory response to lipopolysaccharide. Iron loading increased mitochondrial superoxide production. Treatment with MitoTEMPO, a mitochondria-specific antioxidant, blunted the proinflammatory effects of iron loading. Iron loading increased mitochondrial mass in cells treated with lipopolysaccharide and increased the proportion of nonfunctional mitochondria. Iron loading also altered mitochondrial homeostasis to favor increased production of mitochondria. Conclusions Acute iron loading potentiates the inflammatory response to lipopolysaccharide, at least in part by disrupting mitochondrial homeostasis and increasing the production of mitochondrial superoxide. Improved understanding of iron homeostasis in the context of acute inflammation may yield innovative therapeutic approaches in perioperative and critically ill patients.

show abstract

Defective autophagy impairs ATF3 activity and worsens lung injury during endotoxemia

Abstract: Endotoxemia and sepsis trigger autophagy in lung tissue. Defective autophagy increases mortality and lung inflammation after endotoxemia. Impairment of autophagy results is perinuclear ATF3 sequestration. Starvation ameliorates lung injury by an autophagy-dependent mechanism.

Cited by 44 publications

References 33 publications

Autophagy Protects Against Developing Increased Lung Permeability and Hypoxemia by Down Regulating Inflammasome Activity and IL-1β in LPS Plus Mechanical Ventilation-Induced Acute Lung Injury

Autophagy Protects Against Developing Increased Lung Permeability and Hypoxemia by Down Regulating Inflammasome Activity and IL-1β in LPS Plus Mechanical Ventilation-Induced Acute Lung Injury

Activation of MTOR in pulmonary epithelium promotes LPS-induced acute lung injury

Iron Loading Exaggerates the Inflammatory Response to the Toll-like Receptor 4 Ligand Lipopolysaccharide by Altering Mitochondrial Homeostasis

Contact Info

Product

Resources

About