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Matrikines are key regulators in modulating the amplitude of lung inflammation in acute pulmonary infection.

Akthar S, Patel DF, Beale RC, Peiró T, Xu X, Gaggar A, Jackson PL, Blalock JE, Lloyd CM, Snelgrove RJ - Nat Commun (2015)

Bottom Line: The physiological significance of this secondary anti-inflammatory activity remains unknown.Here we show, using readily resolving pulmonary inflammation models, that loss of this secondary activity leads to more pronounced and sustained inflammation and illness owing to PGP accumulation.This highlights a critical role for the secondary anti-inflammatory activity of LTA4H and thus has consequences for the generation of global LTA4H inhibitors currently being developed.

View Article: PubMed Central - PubMed

Affiliation: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.

ABSTRACT
Bioactive matrix fragments (matrikines) have been identified in a myriad of disorders, but their impact on the evolution of airway inflammation has not been demonstrated. We recently described a pathway where the matrikine and neutrophil chemoattractant proline-glycine-proline (PGP) could be degraded by the enzyme leukotriene A4 hydrolase (LTA4H). LTA4H classically functions in the generation of pro-inflammatory leukotriene B4, thus LTA4H exhibits opposing pro- and anti-inflammatory activities. The physiological significance of this secondary anti-inflammatory activity remains unknown. Here we show, using readily resolving pulmonary inflammation models, that loss of this secondary activity leads to more pronounced and sustained inflammation and illness owing to PGP accumulation. PGP elicits an exacerbated neutrophilic inflammation and protease imbalance that further degrades the extracellular matrix, generating fragments that perpetuate inflammation. This highlights a critical role for the secondary anti-inflammatory activity of LTA4H and thus has consequences for the generation of global LTA4H inhibitors currently being developed.

No MeSH data available.


Related in: MedlinePlus

An absence of LTB4 signalling does not alter pulmonary inflammation but compromises bacterial clearance.Blt1−/− mice and WT controls were infected intranasally with 1 × 107 Hib and weight loss was assessed daily and expressed as a percentage of the original body mass (a). Total cell numbers in the airways (b) and lung tissue (c) of Hib-infected mice were enumerated. The number of neutrophils recruited into the airways (d) and lung tissue (e) of Hib-infected mice was determined by flow cytometry. Bacterial burden was assessed by performing serial dilutions of BALF and lung homogenate, at 6 h (f) and 24 h (g), on Brain Heart Infusion (BHI) agar plates. Phagocytosis of pHrodo-conjugated Hib by alveolar macrophages (h) and neutrophils (i) was assessed by flow cytometry. The capacity of WT and blt1−/− alveolar macrophages (j) and neutrophils (k) to kill Hib was assessed. Hib-infected mice were administered vehicle (PBS), BLT1 antagonist (U-75302) or BLT2 antagonist (LY2552833), and lung neutrophil numbers (l) and c.f.u. (m) were assessed at 24 h post infection. Data (mean±s.e.m.) are representative of at least two experiments with 5–6 mice per group. *P<0.05; **P<0.01 using the Mann–Whitney test.
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f2: An absence of LTB4 signalling does not alter pulmonary inflammation but compromises bacterial clearance.Blt1−/− mice and WT controls were infected intranasally with 1 × 107 Hib and weight loss was assessed daily and expressed as a percentage of the original body mass (a). Total cell numbers in the airways (b) and lung tissue (c) of Hib-infected mice were enumerated. The number of neutrophils recruited into the airways (d) and lung tissue (e) of Hib-infected mice was determined by flow cytometry. Bacterial burden was assessed by performing serial dilutions of BALF and lung homogenate, at 6 h (f) and 24 h (g), on Brain Heart Infusion (BHI) agar plates. Phagocytosis of pHrodo-conjugated Hib by alveolar macrophages (h) and neutrophils (i) was assessed by flow cytometry. The capacity of WT and blt1−/− alveolar macrophages (j) and neutrophils (k) to kill Hib was assessed. Hib-infected mice were administered vehicle (PBS), BLT1 antagonist (U-75302) or BLT2 antagonist (LY2552833), and lung neutrophil numbers (l) and c.f.u. (m) were assessed at 24 h post infection. Data (mean±s.e.m.) are representative of at least two experiments with 5–6 mice per group. *P<0.05; **P<0.01 using the Mann–Whitney test.

Mentions: Physiological functions attributed to LTB4 are relayed through receptor BLT1. To infer the role of LTB4 in our Hib model, wild-type (WT) and blt1−/− mice were infected with 1 × 107 colony-forming unit (c.f.u.) of Hib. WT and blt1−/− mice displayed comparable weight loss (Fig. 2a) and inflammation into the airways (Fig. 2b) and lung parenchyma (Fig. 2c) in response to Hib. Specifically, neutrophilic inflammation into the airways (Fig. 2d) and lung tissue (Fig. 2e) was indistinguishable between Hib-infected WT and blt1−/− mice. Despite comparable cellular inflammation, clearance of Hib was compromised in blt1−/− mice at 6 (Fig. 2f) and 24 h (Fig. 2g) post infection. A plethora of studies have highlighted the capacity of LTB4 to augment the phagocytic and antimicrobial potential of macrophages and neutrophils on a per-cell basis263738394041424344454647484950. Alveolar macrophages (Fig. 2h) and neutrophils (Fig. 2i) from blt1−/− mice exhibited a significant reduction in their capacity to phagocytose pHrodo-labelled Hib relative to WT controls. Furthermore, blt1−/− alveolar macrophages (Fig. 2j) and neutrophils (Fig. 2k) exhibited reduced bacterial killing of Hib on a per-cell basis relative to WT counterparts.


Matrikines are key regulators in modulating the amplitude of lung inflammation in acute pulmonary infection.

Akthar S, Patel DF, Beale RC, Peiró T, Xu X, Gaggar A, Jackson PL, Blalock JE, Lloyd CM, Snelgrove RJ - Nat Commun (2015)

An absence of LTB4 signalling does not alter pulmonary inflammation but compromises bacterial clearance.Blt1−/− mice and WT controls were infected intranasally with 1 × 107 Hib and weight loss was assessed daily and expressed as a percentage of the original body mass (a). Total cell numbers in the airways (b) and lung tissue (c) of Hib-infected mice were enumerated. The number of neutrophils recruited into the airways (d) and lung tissue (e) of Hib-infected mice was determined by flow cytometry. Bacterial burden was assessed by performing serial dilutions of BALF and lung homogenate, at 6 h (f) and 24 h (g), on Brain Heart Infusion (BHI) agar plates. Phagocytosis of pHrodo-conjugated Hib by alveolar macrophages (h) and neutrophils (i) was assessed by flow cytometry. The capacity of WT and blt1−/− alveolar macrophages (j) and neutrophils (k) to kill Hib was assessed. Hib-infected mice were administered vehicle (PBS), BLT1 antagonist (U-75302) or BLT2 antagonist (LY2552833), and lung neutrophil numbers (l) and c.f.u. (m) were assessed at 24 h post infection. Data (mean±s.e.m.) are representative of at least two experiments with 5–6 mice per group. *P<0.05; **P<0.01 using the Mann–Whitney test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4595997&req=5

f2: An absence of LTB4 signalling does not alter pulmonary inflammation but compromises bacterial clearance.Blt1−/− mice and WT controls were infected intranasally with 1 × 107 Hib and weight loss was assessed daily and expressed as a percentage of the original body mass (a). Total cell numbers in the airways (b) and lung tissue (c) of Hib-infected mice were enumerated. The number of neutrophils recruited into the airways (d) and lung tissue (e) of Hib-infected mice was determined by flow cytometry. Bacterial burden was assessed by performing serial dilutions of BALF and lung homogenate, at 6 h (f) and 24 h (g), on Brain Heart Infusion (BHI) agar plates. Phagocytosis of pHrodo-conjugated Hib by alveolar macrophages (h) and neutrophils (i) was assessed by flow cytometry. The capacity of WT and blt1−/− alveolar macrophages (j) and neutrophils (k) to kill Hib was assessed. Hib-infected mice were administered vehicle (PBS), BLT1 antagonist (U-75302) or BLT2 antagonist (LY2552833), and lung neutrophil numbers (l) and c.f.u. (m) were assessed at 24 h post infection. Data (mean±s.e.m.) are representative of at least two experiments with 5–6 mice per group. *P<0.05; **P<0.01 using the Mann–Whitney test.
Mentions: Physiological functions attributed to LTB4 are relayed through receptor BLT1. To infer the role of LTB4 in our Hib model, wild-type (WT) and blt1−/− mice were infected with 1 × 107 colony-forming unit (c.f.u.) of Hib. WT and blt1−/− mice displayed comparable weight loss (Fig. 2a) and inflammation into the airways (Fig. 2b) and lung parenchyma (Fig. 2c) in response to Hib. Specifically, neutrophilic inflammation into the airways (Fig. 2d) and lung tissue (Fig. 2e) was indistinguishable between Hib-infected WT and blt1−/− mice. Despite comparable cellular inflammation, clearance of Hib was compromised in blt1−/− mice at 6 (Fig. 2f) and 24 h (Fig. 2g) post infection. A plethora of studies have highlighted the capacity of LTB4 to augment the phagocytic and antimicrobial potential of macrophages and neutrophils on a per-cell basis263738394041424344454647484950. Alveolar macrophages (Fig. 2h) and neutrophils (Fig. 2i) from blt1−/− mice exhibited a significant reduction in their capacity to phagocytose pHrodo-labelled Hib relative to WT controls. Furthermore, blt1−/− alveolar macrophages (Fig. 2j) and neutrophils (Fig. 2k) exhibited reduced bacterial killing of Hib on a per-cell basis relative to WT counterparts.

Bottom Line: The physiological significance of this secondary anti-inflammatory activity remains unknown.Here we show, using readily resolving pulmonary inflammation models, that loss of this secondary activity leads to more pronounced and sustained inflammation and illness owing to PGP accumulation.This highlights a critical role for the secondary anti-inflammatory activity of LTA4H and thus has consequences for the generation of global LTA4H inhibitors currently being developed.

View Article: PubMed Central - PubMed

Affiliation: Leukocyte Biology Section, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, UK.

ABSTRACT
Bioactive matrix fragments (matrikines) have been identified in a myriad of disorders, but their impact on the evolution of airway inflammation has not been demonstrated. We recently described a pathway where the matrikine and neutrophil chemoattractant proline-glycine-proline (PGP) could be degraded by the enzyme leukotriene A4 hydrolase (LTA4H). LTA4H classically functions in the generation of pro-inflammatory leukotriene B4, thus LTA4H exhibits opposing pro- and anti-inflammatory activities. The physiological significance of this secondary anti-inflammatory activity remains unknown. Here we show, using readily resolving pulmonary inflammation models, that loss of this secondary activity leads to more pronounced and sustained inflammation and illness owing to PGP accumulation. PGP elicits an exacerbated neutrophilic inflammation and protease imbalance that further degrades the extracellular matrix, generating fragments that perpetuate inflammation. This highlights a critical role for the secondary anti-inflammatory activity of LTA4H and thus has consequences for the generation of global LTA4H inhibitors currently being developed.

No MeSH data available.


Related in: MedlinePlus