Role for Cela1 in Postnatal Lung Remodeling and AAT-deficient Emphysema

Rashika Joshi; Andrea Heinz; Qiang Fan; Shuling Guo; Brett Monia; Christian E H Schmelzer; Anthony S Weiss; Matthew Batie; Harikrishnan Parameshwaran; Brian M Varisco

doi:10.1165/rcmb.2017-0361OC

Role for Cela1 in Postnatal Lung Remodeling and AAT-deficient Emphysema

Rashika Joshi, Andrea Heinz, Qiang Fan, Shuling Guo, Brett Monia, Christian E H Schmelzer, Anthony S Weiss, Matthew Batie, Harikrishnan Parameshwaran, Brian M Varisco

9 Citations (Scopus)

Abstract

RATIONALE: α1-antitrypsin (AAT) deficiency-related emphysema is the fourth leading indication for lung transplantation. Chymotrypsin-like elastase 1 (Cela1) is a digestive protease that is expressed during lung development in association with regions of elastin remodeling, exhibits stretch-dependent expression during lung regeneration, and binds lung elastin in a stretch-dependent manner. AAT covalently neutralizes Cela1 in vitro.

OBJECTIVES: We sought to determine the role of Cela1 in postnatal lung physiology, whether it interacted with AAT in vivo, and any effects it may have in the context of AAT deficiency.

METHODS/RESULTS: The lungs of Cela1-/- mice had aberrant lung elastin structure and higher elastance as assessed by Flexivent. Using in situ zymography with ex vivo lung stretch, Cela1 was solely responsible for stretch-inducible lung elastase activity. By mass spectrometry, Cela1 degraded mature elastin similarly to pancreatic elastase. Cela1 promoter and protein sequences were phylogenetically distinct in the placental mammal lineage suggesting an adaptive role for lung-expressed Cela1 in this clade. A six-week antisense oligo mouse model of AAT deficiency resulted in emphysema with increased Cela1 mRNA and reduction in ~70kDa Cela1 consistent with covalent binding of Cela1 by AAT. Cela1-/- mice were completely protected against emphysema in this model. Cela1 was increased in human AAT-deficient emphysema.

CONCLUSIONS: Cela1 is important in physiologic and pathologic stretch-dependent remodeling processes in the postnatal lung. AAT is an important regulator of this process. Our findings provide proof-of-concept for the development of anti-Cela1 therapies to prevent and/or treat AAT-deficient emphysema.

Original language	English
Article number	0361OC
Journal	American Journal of Respiratory Cell and Molecular Biology
Volume	59
Issue number	2
Pages (from-to)	167-178
ISSN	1044-1549
DOIs	https://doi.org/10.1165/rcmb.2017-0361OC
Publication status	Published - 8 Feb 2018

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Journal Article

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10.1165/rcmb.2017-0361OC

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@article{b717a16dad8843ee99dda90f67c56dcb,

title = "Role for Cela1 in Postnatal Lung Remodeling and AAT-deficient Emphysema",

abstract = "RATIONALE: α1-antitrypsin (AAT) deficiency-related emphysema is the fourth leading indication for lung transplantation. Chymotrypsin-like elastase 1 (Cela1) is a digestive protease that is expressed during lung development in association with regions of elastin remodeling, exhibits stretch-dependent expression during lung regeneration, and binds lung elastin in a stretch-dependent manner. AAT covalently neutralizes Cela1 in vitro.OBJECTIVES: We sought to determine the role of Cela1 in postnatal lung physiology, whether it interacted with AAT in vivo, and any effects it may have in the context of AAT deficiency.METHODS/RESULTS: The lungs of Cela1-/- mice had aberrant lung elastin structure and higher elastance as assessed by Flexivent. Using in situ zymography with ex vivo lung stretch, Cela1 was solely responsible for stretch-inducible lung elastase activity. By mass spectrometry, Cela1 degraded mature elastin similarly to pancreatic elastase. Cela1 promoter and protein sequences were phylogenetically distinct in the placental mammal lineage suggesting an adaptive role for lung-expressed Cela1 in this clade. A six-week antisense oligo mouse model of AAT deficiency resulted in emphysema with increased Cela1 mRNA and reduction in ~70kDa Cela1 consistent with covalent binding of Cela1 by AAT. Cela1-/- mice were completely protected against emphysema in this model. Cela1 was increased in human AAT-deficient emphysema.CONCLUSIONS: Cela1 is important in physiologic and pathologic stretch-dependent remodeling processes in the postnatal lung. AAT is an important regulator of this process. Our findings provide proof-of-concept for the development of anti-Cela1 therapies to prevent and/or treat AAT-deficient emphysema.",

keywords = "Journal Article",

author = "Rashika Joshi and Andrea Heinz and Qiang Fan and Shuling Guo and Brett Monia and Schmelzer, {Christian E H} and Weiss, {Anthony S} and Matthew Batie and Harikrishnan Parameshwaran and Varisco, {Brian M}",

year = "2018",

month = feb,

day = "8",

doi = "10.1165/rcmb.2017-0361OC",

language = "English",

volume = "59",

pages = "167--178",

journal = "American Journal of Respiratory Cell and Molecular Biology",

issn = "1044-1549",

publisher = "American Thoracic Society",

number = "2",

}

TY - JOUR

T1 - Role for Cela1 in Postnatal Lung Remodeling and AAT-deficient Emphysema

AU - Joshi, Rashika

AU - Heinz, Andrea

AU - Fan, Qiang

AU - Guo, Shuling

AU - Monia, Brett

AU - Schmelzer, Christian E H

AU - Weiss, Anthony S

AU - Batie, Matthew

AU - Parameshwaran, Harikrishnan

AU - Varisco, Brian M

PY - 2018/2/8

Y1 - 2018/2/8

N2 - RATIONALE: α1-antitrypsin (AAT) deficiency-related emphysema is the fourth leading indication for lung transplantation. Chymotrypsin-like elastase 1 (Cela1) is a digestive protease that is expressed during lung development in association with regions of elastin remodeling, exhibits stretch-dependent expression during lung regeneration, and binds lung elastin in a stretch-dependent manner. AAT covalently neutralizes Cela1 in vitro.OBJECTIVES: We sought to determine the role of Cela1 in postnatal lung physiology, whether it interacted with AAT in vivo, and any effects it may have in the context of AAT deficiency.METHODS/RESULTS: The lungs of Cela1-/- mice had aberrant lung elastin structure and higher elastance as assessed by Flexivent. Using in situ zymography with ex vivo lung stretch, Cela1 was solely responsible for stretch-inducible lung elastase activity. By mass spectrometry, Cela1 degraded mature elastin similarly to pancreatic elastase. Cela1 promoter and protein sequences were phylogenetically distinct in the placental mammal lineage suggesting an adaptive role for lung-expressed Cela1 in this clade. A six-week antisense oligo mouse model of AAT deficiency resulted in emphysema with increased Cela1 mRNA and reduction in ~70kDa Cela1 consistent with covalent binding of Cela1 by AAT. Cela1-/- mice were completely protected against emphysema in this model. Cela1 was increased in human AAT-deficient emphysema.CONCLUSIONS: Cela1 is important in physiologic and pathologic stretch-dependent remodeling processes in the postnatal lung. AAT is an important regulator of this process. Our findings provide proof-of-concept for the development of anti-Cela1 therapies to prevent and/or treat AAT-deficient emphysema.

AB - RATIONALE: α1-antitrypsin (AAT) deficiency-related emphysema is the fourth leading indication for lung transplantation. Chymotrypsin-like elastase 1 (Cela1) is a digestive protease that is expressed during lung development in association with regions of elastin remodeling, exhibits stretch-dependent expression during lung regeneration, and binds lung elastin in a stretch-dependent manner. AAT covalently neutralizes Cela1 in vitro.OBJECTIVES: We sought to determine the role of Cela1 in postnatal lung physiology, whether it interacted with AAT in vivo, and any effects it may have in the context of AAT deficiency.METHODS/RESULTS: The lungs of Cela1-/- mice had aberrant lung elastin structure and higher elastance as assessed by Flexivent. Using in situ zymography with ex vivo lung stretch, Cela1 was solely responsible for stretch-inducible lung elastase activity. By mass spectrometry, Cela1 degraded mature elastin similarly to pancreatic elastase. Cela1 promoter and protein sequences were phylogenetically distinct in the placental mammal lineage suggesting an adaptive role for lung-expressed Cela1 in this clade. A six-week antisense oligo mouse model of AAT deficiency resulted in emphysema with increased Cela1 mRNA and reduction in ~70kDa Cela1 consistent with covalent binding of Cela1 by AAT. Cela1-/- mice were completely protected against emphysema in this model. Cela1 was increased in human AAT-deficient emphysema.CONCLUSIONS: Cela1 is important in physiologic and pathologic stretch-dependent remodeling processes in the postnatal lung. AAT is an important regulator of this process. Our findings provide proof-of-concept for the development of anti-Cela1 therapies to prevent and/or treat AAT-deficient emphysema.

KW - Journal Article

U2 - 10.1165/rcmb.2017-0361OC

DO - 10.1165/rcmb.2017-0361OC

M3 - Journal article

C2 - 29420065

SN - 1044-1549

VL - 59

SP - 167

EP - 178

JO - American Journal of Respiratory Cell and Molecular Biology

JF - American Journal of Respiratory Cell and Molecular Biology

IS - 2

M1 - 0361OC

ER -

Role for Cela1 in Postnatal Lung Remodeling and AAT-deficient Emphysema

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