Combining an epithelial repair factor and anti-fibrotic with a corticosteroid offers optimal treatment for allergic airways disease

K P Patel, A S Giraud, C S Samuel, S G Royce

Research output: Contribution to journalArticleResearchpeer-review

4 Citations (Scopus)

Abstract

BACKGROUND AND PURPOSE: We evaluated the extent to which individual vs combination treatments that specifically targeted airway epithelial damage (with trefoil factor-2/TFF2), airway fibrosis (with serelaxin/RLX) or airway inflammation (AI; with the clinically-used corticosteroid, dexamethasone/DEX) reversed the pathogenesis of chronic allergic airways disease (AAD). 

EXPERIMENTAL APPROACH: Following induction of the 9-week model of ovalbumin (OVA)-induced chronic AAD in 6-8wk female Balb/c mice, animals were i.p.-administered with naphthalene (NA) on d64 to induce epithelial damage; then received daily intranasal (i.n.)-administration of RLX (0.8 mg/ml); TFF2 (0.5 mg/ml); DEX (0.5 mg/ml); RLX + TFF2; or RLX + TFF2 + DEX from d67- 74. On d75, lung function was assessed by invasive plethysmography, before lung tissue was isolated for analyses of various measures. A control group treated with saline + corn oil (CO; vehicle for NA) was also included. 
KEY RESULTS: OVA + NA-injured mice demonstrated significantly increased airway inflammation (AI), AWR (epithelial damage/thickness; subepithelial myofibroblast differentiation, extracellular matrix (ECM) accumulation and fibronectin deposition; as well as total lung collagen concentration); and significantly reduced airway dynamic compliance (cDyn) (all P <0.05 vs saline/CO group). RLX + TFF2 markedly reversed several measures of OVA + NA-induced AWR and normalized the reduction of cDyn (all P <0.05 vs. OVA + NA group). The combined effects of RLX + TFF2 + DEX significantly reversed peribronchial inflammation score, airway epithelial damage, subepithelial ECM/fibronectin deposition and total lung collagen concentration (by 50-90 ); and also normalized the reduction of cDyn (all P <0.05 vs. OVA + NA group). 

CONCLUSIONS AND IMPLICATIONS: Combining an epithelial repair factor and anti-fibrotic provides an effective means of treating the AWR and dysfunction associated with AAD/asthma; and may act as an effective adjunct therapy to anti-inflammatory corticosteroids.
Original languageEnglish
Pages (from-to)2016 - 2029
Number of pages14
JournalBritish Journal of Pharmacology
Volume173
Issue number12
DOIs
Publication statusPublished - 2016

Cite this

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title = "Combining an epithelial repair factor and anti-fibrotic with a corticosteroid offers optimal treatment for allergic airways disease",
abstract = "BACKGROUND AND PURPOSE: We evaluated the extent to which individual vs combination treatments that specifically targeted airway epithelial damage (with trefoil factor-2/TFF2), airway fibrosis (with serelaxin/RLX) or airway inflammation (AI; with the clinically-used corticosteroid, dexamethasone/DEX) reversed the pathogenesis of chronic allergic airways disease (AAD). EXPERIMENTAL APPROACH: Following induction of the 9-week model of ovalbumin (OVA)-induced chronic AAD in 6-8wk female Balb/c mice, animals were i.p.-administered with naphthalene (NA) on d64 to induce epithelial damage; then received daily intranasal (i.n.)-administration of RLX (0.8 mg/ml); TFF2 (0.5 mg/ml); DEX (0.5 mg/ml); RLX + TFF2; or RLX + TFF2 + DEX from d67- 74. On d75, lung function was assessed by invasive plethysmography, before lung tissue was isolated for analyses of various measures. A control group treated with saline + corn oil (CO; vehicle for NA) was also included. KEY RESULTS: OVA + NA-injured mice demonstrated significantly increased airway inflammation (AI), AWR (epithelial damage/thickness; subepithelial myofibroblast differentiation, extracellular matrix (ECM) accumulation and fibronectin deposition; as well as total lung collagen concentration); and significantly reduced airway dynamic compliance (cDyn) (all P <0.05 vs saline/CO group). RLX + TFF2 markedly reversed several measures of OVA + NA-induced AWR and normalized the reduction of cDyn (all P <0.05 vs. OVA + NA group). The combined effects of RLX + TFF2 + DEX significantly reversed peribronchial inflammation score, airway epithelial damage, subepithelial ECM/fibronectin deposition and total lung collagen concentration (by 50-90 ); and also normalized the reduction of cDyn (all P <0.05 vs. OVA + NA group). CONCLUSIONS AND IMPLICATIONS: Combining an epithelial repair factor and anti-fibrotic provides an effective means of treating the AWR and dysfunction associated with AAD/asthma; and may act as an effective adjunct therapy to anti-inflammatory corticosteroids.",
author = "Patel, {K P} and Giraud, {A S} and Samuel, {C S} and Royce, {S G}",
year = "2016",
doi = "10.1111/bph.13494",
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volume = "173",
pages = "2016 -- 2029",
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Combining an epithelial repair factor and anti-fibrotic with a corticosteroid offers optimal treatment for allergic airways disease. / Patel, K P; Giraud, A S; Samuel, C S; Royce, S G.

In: British Journal of Pharmacology, Vol. 173, No. 12, 2016, p. 2016 - 2029.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Combining an epithelial repair factor and anti-fibrotic with a corticosteroid offers optimal treatment for allergic airways disease

AU - Patel, K P

AU - Giraud, A S

AU - Samuel, C S

AU - Royce, S G

PY - 2016

Y1 - 2016

N2 - BACKGROUND AND PURPOSE: We evaluated the extent to which individual vs combination treatments that specifically targeted airway epithelial damage (with trefoil factor-2/TFF2), airway fibrosis (with serelaxin/RLX) or airway inflammation (AI; with the clinically-used corticosteroid, dexamethasone/DEX) reversed the pathogenesis of chronic allergic airways disease (AAD). EXPERIMENTAL APPROACH: Following induction of the 9-week model of ovalbumin (OVA)-induced chronic AAD in 6-8wk female Balb/c mice, animals were i.p.-administered with naphthalene (NA) on d64 to induce epithelial damage; then received daily intranasal (i.n.)-administration of RLX (0.8 mg/ml); TFF2 (0.5 mg/ml); DEX (0.5 mg/ml); RLX + TFF2; or RLX + TFF2 + DEX from d67- 74. On d75, lung function was assessed by invasive plethysmography, before lung tissue was isolated for analyses of various measures. A control group treated with saline + corn oil (CO; vehicle for NA) was also included. KEY RESULTS: OVA + NA-injured mice demonstrated significantly increased airway inflammation (AI), AWR (epithelial damage/thickness; subepithelial myofibroblast differentiation, extracellular matrix (ECM) accumulation and fibronectin deposition; as well as total lung collagen concentration); and significantly reduced airway dynamic compliance (cDyn) (all P <0.05 vs saline/CO group). RLX + TFF2 markedly reversed several measures of OVA + NA-induced AWR and normalized the reduction of cDyn (all P <0.05 vs. OVA + NA group). The combined effects of RLX + TFF2 + DEX significantly reversed peribronchial inflammation score, airway epithelial damage, subepithelial ECM/fibronectin deposition and total lung collagen concentration (by 50-90 ); and also normalized the reduction of cDyn (all P <0.05 vs. OVA + NA group). CONCLUSIONS AND IMPLICATIONS: Combining an epithelial repair factor and anti-fibrotic provides an effective means of treating the AWR and dysfunction associated with AAD/asthma; and may act as an effective adjunct therapy to anti-inflammatory corticosteroids.

AB - BACKGROUND AND PURPOSE: We evaluated the extent to which individual vs combination treatments that specifically targeted airway epithelial damage (with trefoil factor-2/TFF2), airway fibrosis (with serelaxin/RLX) or airway inflammation (AI; with the clinically-used corticosteroid, dexamethasone/DEX) reversed the pathogenesis of chronic allergic airways disease (AAD). EXPERIMENTAL APPROACH: Following induction of the 9-week model of ovalbumin (OVA)-induced chronic AAD in 6-8wk female Balb/c mice, animals were i.p.-administered with naphthalene (NA) on d64 to induce epithelial damage; then received daily intranasal (i.n.)-administration of RLX (0.8 mg/ml); TFF2 (0.5 mg/ml); DEX (0.5 mg/ml); RLX + TFF2; or RLX + TFF2 + DEX from d67- 74. On d75, lung function was assessed by invasive plethysmography, before lung tissue was isolated for analyses of various measures. A control group treated with saline + corn oil (CO; vehicle for NA) was also included. KEY RESULTS: OVA + NA-injured mice demonstrated significantly increased airway inflammation (AI), AWR (epithelial damage/thickness; subepithelial myofibroblast differentiation, extracellular matrix (ECM) accumulation and fibronectin deposition; as well as total lung collagen concentration); and significantly reduced airway dynamic compliance (cDyn) (all P <0.05 vs saline/CO group). RLX + TFF2 markedly reversed several measures of OVA + NA-induced AWR and normalized the reduction of cDyn (all P <0.05 vs. OVA + NA group). The combined effects of RLX + TFF2 + DEX significantly reversed peribronchial inflammation score, airway epithelial damage, subepithelial ECM/fibronectin deposition and total lung collagen concentration (by 50-90 ); and also normalized the reduction of cDyn (all P <0.05 vs. OVA + NA group). CONCLUSIONS AND IMPLICATIONS: Combining an epithelial repair factor and anti-fibrotic provides an effective means of treating the AWR and dysfunction associated with AAD/asthma; and may act as an effective adjunct therapy to anti-inflammatory corticosteroids.

UR - http://www.ncbi.nlm.nih.gov/pubmed/27060978

U2 - 10.1111/bph.13494

DO - 10.1111/bph.13494

M3 - Article

VL - 173

SP - 2016

EP - 2029

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 1476-5381

IS - 12

ER -