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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

Hib-infected lta4h−/− mice display augmented illness and pulmonary inflammation.Lta4h−/− mice and littermate 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). Levels of albumin (b) and lactate dehydrogenase (LDH; c) in the BALF were assessed by ELISA and an enzymatic assay, respectively. Bacterial burden was assessed by performing serial dilutions of BALF (d) and lung homogenate (e) on Brain Heart Infusion (BHI) agar plates. Total cell numbers in the airways (f) and lung tissue (g) of Hib-infected mice was enumerated. The number of neutrophils recruited into the airways (h) and lung tissue (i) of Hib-infected mice was determined by flow cytometry. The number of infiltrating monocytes/macrophages recruited into the airways (j) and lung tissue (k) of Hib-infected mice was determined by flow cytometry. Data (mean±s.e.m.) are combined from two separate experiments with 4–5 mice per group and are representative of 3–4 experiments.*P<0.05; **P<0.01 using the Mann–Whitney test.
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f3: Hib-infected lta4h−/− mice display augmented illness and pulmonary inflammation.Lta4h−/− mice and littermate 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). Levels of albumin (b) and lactate dehydrogenase (LDH; c) in the BALF were assessed by ELISA and an enzymatic assay, respectively. Bacterial burden was assessed by performing serial dilutions of BALF (d) and lung homogenate (e) on Brain Heart Infusion (BHI) agar plates. Total cell numbers in the airways (f) and lung tissue (g) of Hib-infected mice was enumerated. The number of neutrophils recruited into the airways (h) and lung tissue (i) of Hib-infected mice was determined by flow cytometry. The number of infiltrating monocytes/macrophages recruited into the airways (j) and lung tissue (k) of Hib-infected mice was determined by flow cytometry. Data (mean±s.e.m.) are combined from two separate experiments with 4–5 mice per group and are representative of 3–4 experiments.*P<0.05; **P<0.01 using the Mann–Whitney test.

Mentions: Having inferred the role of LTB4 in Hib infection, it was now of interest to determine the phenotype of Hib-infected lta4h−/− mice that lack not only the classical pro-inflammatory LTB4-generating activity but also the anti-inflammatory PGP-degrading activity. WT and lta4h−/− mice were infected with 1 × 107 c.f.u. of Hib and ensuing illness and inflammation assessed. Hib-infected lta4h−/− mice exhibited a more pronounced weight loss that was slower to resolve relative to WT controls (Fig. 3a). In keeping with a more pronounced illness in lta4h−/− mice, they also displayed augmented pulmonary oedema (Fig. 3b) and cellular damage (Fig. 3c). The more pronounced illness observed in Hib-infected lta4h−/− mice relative to WT controls was not attributable to compromised bacterial clearance, as c.f.u. were comparable in BALF (Fig. 3d) and lung parenchyma (Fig. 3e). Instead, Hib-infected lta4h−/− mice showed a marked increase in cellular infiltrate into their airways (Fig. 3f) and lung tissue (Fig. 3g) relative to the WT animals, which was largely attributable to a substantial increase in neutrophils (Fig. 3h,i). Secondary to the augmented neutrophilia seen in lta4h−/− mice was an elevated infiltration of monocytes/macrophages into the airways (Fig. 3j) and lung tissue (Fig. 3k) relative to WT controls.


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)

Hib-infected lta4h−/− mice display augmented illness and pulmonary inflammation.Lta4h−/− mice and littermate 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). Levels of albumin (b) and lactate dehydrogenase (LDH; c) in the BALF were assessed by ELISA and an enzymatic assay, respectively. Bacterial burden was assessed by performing serial dilutions of BALF (d) and lung homogenate (e) on Brain Heart Infusion (BHI) agar plates. Total cell numbers in the airways (f) and lung tissue (g) of Hib-infected mice was enumerated. The number of neutrophils recruited into the airways (h) and lung tissue (i) of Hib-infected mice was determined by flow cytometry. The number of infiltrating monocytes/macrophages recruited into the airways (j) and lung tissue (k) of Hib-infected mice was determined by flow cytometry. Data (mean±s.e.m.) are combined from two separate experiments with 4–5 mice per group and are representative of 3–4 experiments.*P<0.05; **P<0.01 using the Mann–Whitney test.
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f3: Hib-infected lta4h−/− mice display augmented illness and pulmonary inflammation.Lta4h−/− mice and littermate 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). Levels of albumin (b) and lactate dehydrogenase (LDH; c) in the BALF were assessed by ELISA and an enzymatic assay, respectively. Bacterial burden was assessed by performing serial dilutions of BALF (d) and lung homogenate (e) on Brain Heart Infusion (BHI) agar plates. Total cell numbers in the airways (f) and lung tissue (g) of Hib-infected mice was enumerated. The number of neutrophils recruited into the airways (h) and lung tissue (i) of Hib-infected mice was determined by flow cytometry. The number of infiltrating monocytes/macrophages recruited into the airways (j) and lung tissue (k) of Hib-infected mice was determined by flow cytometry. Data (mean±s.e.m.) are combined from two separate experiments with 4–5 mice per group and are representative of 3–4 experiments.*P<0.05; **P<0.01 using the Mann–Whitney test.
Mentions: Having inferred the role of LTB4 in Hib infection, it was now of interest to determine the phenotype of Hib-infected lta4h−/− mice that lack not only the classical pro-inflammatory LTB4-generating activity but also the anti-inflammatory PGP-degrading activity. WT and lta4h−/− mice were infected with 1 × 107 c.f.u. of Hib and ensuing illness and inflammation assessed. Hib-infected lta4h−/− mice exhibited a more pronounced weight loss that was slower to resolve relative to WT controls (Fig. 3a). In keeping with a more pronounced illness in lta4h−/− mice, they also displayed augmented pulmonary oedema (Fig. 3b) and cellular damage (Fig. 3c). The more pronounced illness observed in Hib-infected lta4h−/− mice relative to WT controls was not attributable to compromised bacterial clearance, as c.f.u. were comparable in BALF (Fig. 3d) and lung parenchyma (Fig. 3e). Instead, Hib-infected lta4h−/− mice showed a marked increase in cellular infiltrate into their airways (Fig. 3f) and lung tissue (Fig. 3g) relative to the WT animals, which was largely attributable to a substantial increase in neutrophils (Fig. 3h,i). Secondary to the augmented neutrophilia seen in lta4h−/− mice was an elevated infiltration of monocytes/macrophages into the airways (Fig. 3j) and lung tissue (Fig. 3k) relative to WT controls.

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