PI3-K and Akt in Acute Lung Injury

  • Geraci, Mark, (PI)
  • Nick, Jerry (PI)
  • Leung, Donald (PI)
  • Abraham, Edward (PI)
  • Dinarello, Charles Anthony (PI)

Project: Research project

Description

DESCRIPTION (provided by the applicant):
Acute lung injury (ALI) is characterized by the accumulation of activated neutrophils in the
lungs. These pulmonary neutrophils express proinflammatory cytokines and show increased
activation of the transcriptional regulatory factor NF-kB. NF-kB is activated in the lungs of
patients with ARDS and, in experimental models, inhibition of NF-kB prevents the development
of ALI. The serine/threonine kinase Akt/protein kinase B and the immediate upstream kinase,
phosphoinositide 3-kinase (PI3-K), occupy central roles in pathways regulating activation of NFkB as well as expression of proinflammatory mediators, including cytokines. Because of the
pivotal position that NF-kB has in modulating inflammatory processes, the degree of activation
of PI3-K, Akt, and NF-kB in lung neutrophils may be important in determining the intensity of
acute inflammatory responses in the lungs after exposure to relevant clinical stimuli, such as
endotoxin and proinflammatory cytokines. Our hypothesis is that neutrophil phenotypes
characterized by enhanced activation of PI3-K, Akt, and NF-kB in response to proinflammatory
stimuli are associated with increased pulmonary inflammation, a greater likelihood of
developing acute lung injury, and worse outcome from acute lung injury. Patients whose
neutrophils are of a high responder phenotype, as defined by increased levels of PI3-K, Akt, and
NF-kB activation in response to relevant stimuli, such as LPS or cytokines, would be hypothesized not only to be at higher risk of developing ALI, but also to have more severe ALI than patients with low responder phenotypes.
The specific aims of this project are: 1) To define high and low responder neutrophil phenotypes
in humans as determined by the activation of NF-kB, Akt, and related genes, in human
peripheral blood neutrophils exposed to proinflammatory stimuli; 2) To determine if the degree
of activation of NF-kB, Akt, and related genes in neutrophils stimulated in vitro by
proinflammatory stimuli or under basal unstimulated conditions predicts a) the intensity of the in
vivo pulmonary inflammatory response in humans given endotoxin into the lungs; b) the
development and severity of acute lung injury in at risk patients; c) the severity of pulmonary
dysfunction in patients with ALI; 3) To examine the roles that PI3-K and Akt play in modulating
activation of NF-kB in neutrophils as well as the intensity and duration of acute in vivo pulmonary
inflammatory responses. The overall goal of the proposed experiments is to define genetic,
signaling, and transcriptional regulatory mechanisms induced in neutrophils and involving PI3-K,
Akt and NF-kB that contribute to and/or predict the development and severity of acute lung
injury. The elucidation of fundamental mechanisms that modulate neutrophil function and that
involve PI3-K, Akt, and NF-kB should advance understanding of the causes, treatment, and
prevention of ALI and ARDS.
StatusFinished
Effective start/end date7/1/026/30/08

Funding

  • National Institutes of Health
  • National Institutes of Health

Fingerprint

Molecular Biology
Neutrophils
Bronchoalveolar Lavage
Gene Expression
Endotoxins
Healthy Volunteers
Reference Values
Immunochemistry
Acute Lung Injury
Multigene Family
Oligonucleotide Array Sequence Analysis
Genes
In Situ Hybridization
Cluster Analysis
Real-Time Polymerase Chain Reaction
History
Databases

Keywords

  • Medicine(all)