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Proline-Glycine-Proline (PGP) and High Mobility Group Box Protein-1 (HMGB1): Potential Mediators of Cystic Fibrosis Airway Inflammation.

Gaggar A, Rowe SM, Matthew H, Blalock JE - Open Respir Med J (2010)

Bottom Line: This inflammation leads to extracellular matrix (ECM) remodeling and eventually to the development of bronchiectasis.It will then focus on these molecules in a murine model of CF-like airway disease and in human biological specimens from CF individuals.Finally, this manuscript will address possible mechanisms for therapeutic targeting of these bioactive mediators.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, AL.

ABSTRACT
Cystic fibrosis (CF) is chronic lung disease characterized by an unrelenting neutrophil-predominant airway inflammatory response. This inflammation leads to extracellular matrix (ECM) remodeling and eventually to the development of bronchiectasis. While many components of the immune response in CF have been well-characterized, recent data suggests that small molecules may play an important and underappreciated role in this inflammation. This review will examine two novel molecules: proline-glycine-proline (PGP) and high mobility group box protein-1 (HMGB1), and their potential impact in CF lung disease. This review will provide a brief overview of CF lung disease and background on both HMGB1 and PGP. It will then focus on these molecules in a murine model of CF-like airway disease and in human biological specimens from CF individuals. Finally, this manuscript will address possible mechanisms for therapeutic targeting of these bioactive mediators.

No MeSH data available.


Related in: MedlinePlus

PGP and HMGB1 in the CF airway. Two potential pathways that may link airway expression of PGP and HMGB1 are shown. (A): Neutrophils are recruited to the airway by inflammatory stimuli and eventually undergo necrosis. Release of HMGB1 during necrosis is accompanied by concurrent but independent activation of proteases MMP-9 and prolyl endopeptidase, each required for the generation of PGP. (B): Extracellular HMGB1 activates airway macrophages through a TLR and/or RAGE dependent pathway, resulting in the release of MMP-9 and prolyl endopeptidase and generation of PGP, which perpetuate the inflammatory process.
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Figure 1: PGP and HMGB1 in the CF airway. Two potential pathways that may link airway expression of PGP and HMGB1 are shown. (A): Neutrophils are recruited to the airway by inflammatory stimuli and eventually undergo necrosis. Release of HMGB1 during necrosis is accompanied by concurrent but independent activation of proteases MMP-9 and prolyl endopeptidase, each required for the generation of PGP. (B): Extracellular HMGB1 activates airway macrophages through a TLR and/or RAGE dependent pathway, resulting in the release of MMP-9 and prolyl endopeptidase and generation of PGP, which perpetuate the inflammatory process.

Mentions: One interesting question that has evolved from the Scnn1b+ transgenic mice data is whether HMGB1 may serve to directly (or indirectly) generate PGP in vivo (Fig. 1). While it is unlikely that PGP is directly liberated from collagen by HMGB1, it is entirely possible that HMGB1 may induce the release of proteases from inflammatory cell populations, leading to the cleavage of PGP from intact collagen (Panel B). However, it is also possible that during necrosis of inflammatory cells, proteases are released along with HMGB1 and that HMGB1 has no direct influence on PGP production, but is rather a marker of cellular necrosis (Panel A). Clarification of these points may allow for an improved understanding if these pathways may overlap, highlighting potentially interesting therapeutic targets.


Proline-Glycine-Proline (PGP) and High Mobility Group Box Protein-1 (HMGB1): Potential Mediators of Cystic Fibrosis Airway Inflammation.

Gaggar A, Rowe SM, Matthew H, Blalock JE - Open Respir Med J (2010)

PGP and HMGB1 in the CF airway. Two potential pathways that may link airway expression of PGP and HMGB1 are shown. (A): Neutrophils are recruited to the airway by inflammatory stimuli and eventually undergo necrosis. Release of HMGB1 during necrosis is accompanied by concurrent but independent activation of proteases MMP-9 and prolyl endopeptidase, each required for the generation of PGP. (B): Extracellular HMGB1 activates airway macrophages through a TLR and/or RAGE dependent pathway, resulting in the release of MMP-9 and prolyl endopeptidase and generation of PGP, which perpetuate the inflammatory process.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2864429&req=5

Figure 1: PGP and HMGB1 in the CF airway. Two potential pathways that may link airway expression of PGP and HMGB1 are shown. (A): Neutrophils are recruited to the airway by inflammatory stimuli and eventually undergo necrosis. Release of HMGB1 during necrosis is accompanied by concurrent but independent activation of proteases MMP-9 and prolyl endopeptidase, each required for the generation of PGP. (B): Extracellular HMGB1 activates airway macrophages through a TLR and/or RAGE dependent pathway, resulting in the release of MMP-9 and prolyl endopeptidase and generation of PGP, which perpetuate the inflammatory process.
Mentions: One interesting question that has evolved from the Scnn1b+ transgenic mice data is whether HMGB1 may serve to directly (or indirectly) generate PGP in vivo (Fig. 1). While it is unlikely that PGP is directly liberated from collagen by HMGB1, it is entirely possible that HMGB1 may induce the release of proteases from inflammatory cell populations, leading to the cleavage of PGP from intact collagen (Panel B). However, it is also possible that during necrosis of inflammatory cells, proteases are released along with HMGB1 and that HMGB1 has no direct influence on PGP production, but is rather a marker of cellular necrosis (Panel A). Clarification of these points may allow for an improved understanding if these pathways may overlap, highlighting potentially interesting therapeutic targets.

Bottom Line: This inflammation leads to extracellular matrix (ECM) remodeling and eventually to the development of bronchiectasis.It will then focus on these molecules in a murine model of CF-like airway disease and in human biological specimens from CF individuals.Finally, this manuscript will address possible mechanisms for therapeutic targeting of these bioactive mediators.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, AL.

ABSTRACT
Cystic fibrosis (CF) is chronic lung disease characterized by an unrelenting neutrophil-predominant airway inflammatory response. This inflammation leads to extracellular matrix (ECM) remodeling and eventually to the development of bronchiectasis. While many components of the immune response in CF have been well-characterized, recent data suggests that small molecules may play an important and underappreciated role in this inflammation. This review will examine two novel molecules: proline-glycine-proline (PGP) and high mobility group box protein-1 (HMGB1), and their potential impact in CF lung disease. This review will provide a brief overview of CF lung disease and background on both HMGB1 and PGP. It will then focus on these molecules in a murine model of CF-like airway disease and in human biological specimens from CF individuals. Finally, this manuscript will address possible mechanisms for therapeutic targeting of these bioactive mediators.

No MeSH data available.


Related in: MedlinePlus