p55PIK deficiency and its NH2-terminal derivative inhibit inflammation and emphysema in COPD mouse model.
Am J Physiol Lung Cell Mol Physiol
; 321(1): L159-L173, 2021 07 01.
Article
em En
| MEDLINE
| ID: mdl-33949204
ABSTRACT
Chronic obstructive pulmonary disease (COPD) is composed of chronic airway inflammation and emphysema. Recent studies show that Class IA phosphatidylinositol 3-kinases (PI3Ks) play an important role in the regulation of inflammation and emphysema. However, there are few studies on their regulatory subunits. p55PIK is a regulatory subunit of Class IA PI3Ks, and its unique NH2-terminal gives it special functions. p55PIK expression in the lungs of nonsmokers, smokers, and patients with COPD was examined. We established a fusion protein TAT-N15 from the NH2-terminal effector sequence of p55PIK and TAT (the transduction domain of HIV transactivator protein) and investigated the effects of silencing p55PIK or adding TAT-N15 on cigarette smoke exposure at the cellular and animal level. p55PIK expression was increased in patients with COPD. p55PIK deficiency and TAT-N15 significantly inhibited the cigarette smoke extract-induced IL-6, IL-8, and activation of the Akt and the NF-κB pathway in BEAS-2B. p55PIK deficiency and TAT-N15 intranasal administration prevented emphysema and the lung function decline in mice exposed to smoke for 6 mo. p55PIK deficiency and TAT-N15 significantly inhibited lung inflammatory infiltration, reduced levels of IL-6 and KC in mice lung homogenate, and inhibited activation of the Akt and the NF-κB signaling in COPD mice lungs. Our studies indicate that p55PIK is involved in the pathogenesis of COPD, and its NH2-terminal derivative TAT-N15 could be an effective drug in the treatment of COPD by inhibiting the activation of the Akt and the NF-κB pathway.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Enfisema Pulmonar
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Fumaça
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Fosfatidilinositol 3-Quinases
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Doença Pulmonar Obstrutiva Crônica
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Inflamação
Tipo de estudo:
Etiology_studies
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Observational_studies
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Risk_factors_studies
Limite:
Adult
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Aged
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Animals
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Am J Physiol Lung Cell Mol Physiol
Ano de publicação:
2021
Tipo de documento:
Article