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Platelets from Asthmatic Individuals Show Less Reliance on Glycolysis.

Xu W, Cardenes N, Corey C, Erzurum SC, Shiva S - PLoS ONE (2015)

Bottom Line: Further, several studies demonstrate altered mitochondrial function in asthmatic airways and suggest that these changes may be systemic.However, it is unknown whether systemic metabolic changes can be detected in circulating cells in asthmatic patients.The implications for this potential metabolic shift will be discussed in the context of increased oxidative stress and hypoxic adaptation of asthmatic patients.

View Article: PubMed Central - PubMed

Affiliation: Lerner Research Institute, Cleveland, Ohio, United States of America.

ABSTRACT
Asthma, a chronic inflammatory airway disease, is typified by high levels of TH2-cytokines and excessive generation of reactive nitrogen and oxygen species, which contribute to bronchial epithelial injury and airway remodeling. While immune function plays a major role in the pathogenesis of the disease, accumulating evidence suggests that altered cellular metabolism is a key determinant in the predisposition and disease progression of asthma. Further, several studies demonstrate altered mitochondrial function in asthmatic airways and suggest that these changes may be systemic. However, it is unknown whether systemic metabolic changes can be detected in circulating cells in asthmatic patients. Platelets are easily accessible blood cells that are known to propagate airway inflammation in asthma. Here we perform a bioenergetic screen of platelets from asthmatic and healthy individuals and demonstrate that asthmatic platelets show a decreased reliance on glycolytic processes and have increased tricarboxylic acid cycle activity. These data demonstrate a systemic alteration in asthma and are consistent with prior reports suggesting that oxidative phosphorylation is more efficient asthmatic individuals. The implications for this potential metabolic shift will be discussed in the context of increased oxidative stress and hypoxic adaptation of asthmatic patients. Further, these data suggest that platelets are potentially a good model for the monitoring of bioenergetic changes in asthma.

No MeSH data available.


Related in: MedlinePlus

Platelets show decreased glycolytic rate in asthma.(A) Extracellular acidification rate (ECAR) trace in asthmatic (filled squares) and healthy controls (open squares) basally, after the addition of oligomycin A, FCCP and 2-DG. (B) Quantification of ECAR basally, after oligomycin A addition and 2DG treatment in healthy controls (open bars) and asthmatic platelets (filled bars). (C-D) ECAR basally and after oligomycin A addition for platelets from each (C) healthy control subject and (D) asthmatic individuals. (E) Quantification of the difference in ECAR from basal to oligomycin A addition in healthy (control)(white bar) and asthmatic individuals (black bar). (F) The change in ECAR as a function of OCR in healthy (open circles) and asthmatic (filled squares) platelets basally and after the addition of oligomycin A. Arrows show the shift in ECAR/OCR after oligomycin A addition. n = 12 asthma, n = 13 controls; *p<0.01; #p<0.05.
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pone.0132007.g004: Platelets show decreased glycolytic rate in asthma.(A) Extracellular acidification rate (ECAR) trace in asthmatic (filled squares) and healthy controls (open squares) basally, after the addition of oligomycin A, FCCP and 2-DG. (B) Quantification of ECAR basally, after oligomycin A addition and 2DG treatment in healthy controls (open bars) and asthmatic platelets (filled bars). (C-D) ECAR basally and after oligomycin A addition for platelets from each (C) healthy control subject and (D) asthmatic individuals. (E) Quantification of the difference in ECAR from basal to oligomycin A addition in healthy (control)(white bar) and asthmatic individuals (black bar). (F) The change in ECAR as a function of OCR in healthy (open circles) and asthmatic (filled squares) platelets basally and after the addition of oligomycin A. Arrows show the shift in ECAR/OCR after oligomycin A addition. n = 12 asthma, n = 13 controls; *p<0.01; #p<0.05.

Mentions: To determine whether glycolytic rate differed in asthma, we next compared basal glycolysis in platelets from asthma and healthy controls (Fig 4A and 4B). Evaluation of glycolysis was based on the measurement of extracellular acidification rate (ECAR), which increases due to glycolysis-dependent cellular proton production and export, a process that correlates with lactic acid formation. Basal ECAR in platelets from asthmatics (16.0±1.2 mpH/min/106 platelets) was significantly lower than control platelets (23.5±1.9 mpH/min/106 platelets)(Fig 4A and 4B). ECAR in both groups was inhibited ~99% by 2-DG as expected. Further, when ATP production by oxidative phosphorylation was inhibited using oligomycin A, there was a small but statistically significant increase in glycolytic rate (compared to basal rate) in each subject of both the healthy control (Fig 4C; P = 0.005) and asthmatic (Fig 4D; P<0.001) groups. Notably, this oligomycin A-induced increase (calculated by subtracting basal rate from oligomycin rate for each subject) was significantly greater in platelets from asthmatic than control individuals (Fig 4E). Thus, the relationship of ECAR/OCR is shifted in asthmatics compared to healthy controls in the presence of oligomycin (Fig 4F). These data suggest that platelets from asthmatic individuals show less reliance on glycolysis (and are more oxidative) than those from control subjects.


Platelets from Asthmatic Individuals Show Less Reliance on Glycolysis.

Xu W, Cardenes N, Corey C, Erzurum SC, Shiva S - PLoS ONE (2015)

Platelets show decreased glycolytic rate in asthma.(A) Extracellular acidification rate (ECAR) trace in asthmatic (filled squares) and healthy controls (open squares) basally, after the addition of oligomycin A, FCCP and 2-DG. (B) Quantification of ECAR basally, after oligomycin A addition and 2DG treatment in healthy controls (open bars) and asthmatic platelets (filled bars). (C-D) ECAR basally and after oligomycin A addition for platelets from each (C) healthy control subject and (D) asthmatic individuals. (E) Quantification of the difference in ECAR from basal to oligomycin A addition in healthy (control)(white bar) and asthmatic individuals (black bar). (F) The change in ECAR as a function of OCR in healthy (open circles) and asthmatic (filled squares) platelets basally and after the addition of oligomycin A. Arrows show the shift in ECAR/OCR after oligomycin A addition. n = 12 asthma, n = 13 controls; *p<0.01; #p<0.05.
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Related In: Results  -  Collection

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pone.0132007.g004: Platelets show decreased glycolytic rate in asthma.(A) Extracellular acidification rate (ECAR) trace in asthmatic (filled squares) and healthy controls (open squares) basally, after the addition of oligomycin A, FCCP and 2-DG. (B) Quantification of ECAR basally, after oligomycin A addition and 2DG treatment in healthy controls (open bars) and asthmatic platelets (filled bars). (C-D) ECAR basally and after oligomycin A addition for platelets from each (C) healthy control subject and (D) asthmatic individuals. (E) Quantification of the difference in ECAR from basal to oligomycin A addition in healthy (control)(white bar) and asthmatic individuals (black bar). (F) The change in ECAR as a function of OCR in healthy (open circles) and asthmatic (filled squares) platelets basally and after the addition of oligomycin A. Arrows show the shift in ECAR/OCR after oligomycin A addition. n = 12 asthma, n = 13 controls; *p<0.01; #p<0.05.
Mentions: To determine whether glycolytic rate differed in asthma, we next compared basal glycolysis in platelets from asthma and healthy controls (Fig 4A and 4B). Evaluation of glycolysis was based on the measurement of extracellular acidification rate (ECAR), which increases due to glycolysis-dependent cellular proton production and export, a process that correlates with lactic acid formation. Basal ECAR in platelets from asthmatics (16.0±1.2 mpH/min/106 platelets) was significantly lower than control platelets (23.5±1.9 mpH/min/106 platelets)(Fig 4A and 4B). ECAR in both groups was inhibited ~99% by 2-DG as expected. Further, when ATP production by oxidative phosphorylation was inhibited using oligomycin A, there was a small but statistically significant increase in glycolytic rate (compared to basal rate) in each subject of both the healthy control (Fig 4C; P = 0.005) and asthmatic (Fig 4D; P<0.001) groups. Notably, this oligomycin A-induced increase (calculated by subtracting basal rate from oligomycin rate for each subject) was significantly greater in platelets from asthmatic than control individuals (Fig 4E). Thus, the relationship of ECAR/OCR is shifted in asthmatics compared to healthy controls in the presence of oligomycin (Fig 4F). These data suggest that platelets from asthmatic individuals show less reliance on glycolysis (and are more oxidative) than those from control subjects.

Bottom Line: Further, several studies demonstrate altered mitochondrial function in asthmatic airways and suggest that these changes may be systemic.However, it is unknown whether systemic metabolic changes can be detected in circulating cells in asthmatic patients.The implications for this potential metabolic shift will be discussed in the context of increased oxidative stress and hypoxic adaptation of asthmatic patients.

View Article: PubMed Central - PubMed

Affiliation: Lerner Research Institute, Cleveland, Ohio, United States of America.

ABSTRACT
Asthma, a chronic inflammatory airway disease, is typified by high levels of TH2-cytokines and excessive generation of reactive nitrogen and oxygen species, which contribute to bronchial epithelial injury and airway remodeling. While immune function plays a major role in the pathogenesis of the disease, accumulating evidence suggests that altered cellular metabolism is a key determinant in the predisposition and disease progression of asthma. Further, several studies demonstrate altered mitochondrial function in asthmatic airways and suggest that these changes may be systemic. However, it is unknown whether systemic metabolic changes can be detected in circulating cells in asthmatic patients. Platelets are easily accessible blood cells that are known to propagate airway inflammation in asthma. Here we perform a bioenergetic screen of platelets from asthmatic and healthy individuals and demonstrate that asthmatic platelets show a decreased reliance on glycolytic processes and have increased tricarboxylic acid cycle activity. These data demonstrate a systemic alteration in asthma and are consistent with prior reports suggesting that oxidative phosphorylation is more efficient asthmatic individuals. The implications for this potential metabolic shift will be discussed in the context of increased oxidative stress and hypoxic adaptation of asthmatic patients. Further, these data suggest that platelets are potentially a good model for the monitoring of bioenergetic changes in asthma.

No MeSH data available.


Related in: MedlinePlus