Management of Acute Lung Injury: Palmitoylethanolamide as a New Approach

Peritore, Alessio Filippo; D’Amico, Ramona; Siracusa, Rosalba; Cordaro, Marika; Fusco, Roberta; Gugliandolo, Enrico; Genovese, Tiziana; Crupi, Rosalia; Paola, Rosanna Di; Cuzzocrea, Salvatore; Impellizzeri, Daniela

doi:10.3390/ijms22115533

Cited by 48 publications

(45 citation statements)

References 71 publications

(75 reference statements)

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“…Previous studies indicate that inhibition of the chemokine CXC-CXCR receptor axis prevents neutrophil recruitment and tissue injury in several sterile inflammationinduced ALI animal models [1]. A recent study shows that palmitoylethanolamide inhibits ALI in mice induced by endotoxin lipopolysaccharide (LPS) and may represent a potential adjuvant anti-inflammatory therapeutic for treating lung injury [6]. Besides the involvement of inflammation, necroptosis, a form of programmed lytic cell death, has emerged as a driving factor in the pathogenesis of ALI [7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Interferon-γ Preferentially Promotes Necroptosis of Lung Epithelial Cells by Upregulating MLKL

Qin

Shetty

Tucker

et al. 2022

Cells

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Necroptosis, a form of programmed lytic cell death, has emerged as a driving factor in the pathogenesis of acute lung injury (ALI). As ALI is often associated with a cytokine storm, we determined whether pro-inflammatory cytokines modulate the susceptibility of lung cells to necroptosis and which mediators dominate to control necroptosis. In this study, we pretreated/primed mouse primary lung epithelial and endothelial cells with various inflammatory mediators and assessed cell type-dependent responses to different necroptosis inducers and their underlying mechanisms. We found that interferon-γ (IFNγ) as low as 1 ng/mL preferentially promoted necroptosis and accelerated the release of damage-associated molecular patterns from primary alveolar and airway epithelial cells but not lung microvascular endothelial cells. Type-I IFNα was about fifty-fold less effective than IFNγ. Conversely, TNFα or agonists of Toll-like receptor-3 (TLR3), TLR4, TLR7 and TLR9 had a minor effect. The enhanced necroptosis in IFNγ-activated lung epithelial cells was dependent on IFNγ signaling and receptor-interacting protein kinase-3. We further showed that necroptosis effector mixed lineage kinase domain-like protein (MLKL) was predominantly induced by IFNγ, contributing to the enhanced necroptosis in lung epithelial cells. Collectively, our findings indicate that IFNγ is a potent enhancer of lung epithelial cell susceptibility to necroptosis.

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Section: Introductionmentioning

confidence: 99%

Interferon-γ Preferentially Promotes Necroptosis of Lung Epithelial Cells by Upregulating MLKL

Qin

Shetty

Tucker

et al. 2022

Cells

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“…The dose of um-PEA was selected based on previous studies [ 54 , 55 ]. Rats were euthanized 12 h after LPS infusion and lungs were harvested for further analysis.…”

Section: Methodsmentioning

confidence: 99%

Ultramicronized Palmitoylethanolamide in the Management of Sepsis-Induced Coagulopathy and Disseminated Intravascular Coagulation

D’Amico

Monaco

Siracusa

et al. 2021

IJMS

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Disseminated intravascular coagulation (DIC) is a severe condition characterized by the systemic formation of microthrombi complicated with bleeding tendency and organ dysfunction. In the last years, it represents one of the most frequent consequences of coronavirus disease 2019 (COVID-19). The pathogenesis of DIC is complex, with cross-talk between the coagulant and inflammatory pathways. The objective of this study is to investigate the anti-inflammatory action of ultramicronized palmitoylethanolamide (um-PEA) in a lipopolysaccharide (LPS)-induced DIC model in rats. Experimental DIC was induced by continual infusion of LPS (30 mg/kg) for 4 h through the tail vein. Um-PEA (30 mg/kg) was given orally 30 min before and 1 h after the start of intravenous infusion of LPS. Results showed that um-PEA reduced alteration of coagulation markers, as well as proinflammatory cytokine release in plasma and lung samples, induced by LPS infusion. Furthermore, um-PEA also has the effect of preventing the formation of fibrin deposition and lung damage. Moreover, um-PEA was able to reduce the number of mast cells (MCs) and the release of its serine proteases, which are also necessary for SARS-CoV-2 infection. These results suggest that um-PEA could be considered as a potential therapeutic approach in the management of DIC and in clinical implications associated to coagulopathy and lung dysfunction, such as COVID-19.

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“…Acute lung injury (ALI) is a life-threatening pulmonary syndrome with high incidence and mortality worldwide and is also the most serious form of lung injury caused by the current pandemic coronavirus disease 2019 (COVID-19) ( Peck and Hibbert, 2019 ; Peritore et al, 2021 ). The leading causes of ALI include bacterial infection, acid inhalation, fatty embolism, or virus infection.…”

Section: Introductionmentioning

confidence: 99%

Protective Effect of Fluorofenidone Against Acute Lung Injury Through Suppressing the MAPK/NF-κB Pathway

Lv¹,

Yao²,

He³

et al. 2021

Front. Pharmacol.

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Acute lung injury (ALI) is a severe disease that presents serious damage and excessive inflammation in lungs with high mortality without effective pharmacological therapy. Fluorofenidone (AKFPD) is a novel pyridone agent that has anti-fibrosis, anti-inflammation, and other pharmacological activities, while the effect of fluorofenidone on ALI is unclarified. Here, we elucidated the protective effects and underlying mechanism of fluorofenidone on lipopolysaccharide (LPS)-induced ALI. In this study, fluorofenidone alleviated lung tissue structure injury and reduced mortality, decreased the pulmonary inflammatory cell accumulation and level of inflammatory cytokines IL-1β, IL-6, and TNF-α in the bronchoalveolar lavage fluid, and attenuated pulmonary apoptosis in LPS-induced ALI mice. Moreover, fluorofenidone could block LPS-activated phosphorylation of ERK, JNK, and P38 and further inhibited the phosphorylation of IκB and P65. These results suggested that fluorofenidone can significantly contrast LPS-induced ALI through suppressing the activation of the MAPK/NF-κB signaling pathway, which indicates that fluorofenidone could be considered as a novel therapeutic candidate for ALI.

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Management of Acute Lung Injury: Palmitoylethanolamide as a New Approach

Cited by 48 publications

References 71 publications

Interferon-γ Preferentially Promotes Necroptosis of Lung Epithelial Cells by Upregulating MLKL

Interferon-γ Preferentially Promotes Necroptosis of Lung Epithelial Cells by Upregulating MLKL

Ultramicronized Palmitoylethanolamide in the Management of Sepsis-Induced Coagulopathy and Disseminated Intravascular Coagulation

Protective Effect of Fluorofenidone Against Acute Lung Injury Through Suppressing the MAPK/NF-κB Pathway

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