Epithelial cell proliferation contributes to airway remodeling in severe asthma

Lance Cohen; E. Xueping; Jaime Tarsi; Thiruvamoor Ramkumar; Todd K. Horiuchi; Rebecca Cochran; Steve DeMartino; Kenneth B. Schechtman; Iftikhar Hussain; Michael J. Holtzman; Mario Castro; Elliot Israel; Bruce D. Levy; Gautham Marigowda; Serpil C. Erzurum; Raed A. Dweik; Suzy A.A. Comhair; Abigail R. Lara; Marcelle Baaklini; Daniel Laskowski; Jacqueline Pyle; W. Gerald Teague; Anne M. Fitzpatrick; Eric Hunter; Kian F. Chung; Mark Hew; Alfonso Torrego; Sally Meah; Mun Lim; Sally E. Wenzel; Diane Rhodes; William J. Calhoun; Melissa P. Clark; Renee Folger; Rebecca Z. Wade; Bill T. Ameredes; Dori Smith; Benjamin Gaston; Peter Urban; William W. Busse; Nizar Jarjour; Erin Billmeyer; Cheri Swenson; Gina Crisafi; Eugene R. Bleecker; Deborah Meyers; Wendy Moore; Stephen Peters; Annette Hastie; Gregory Hawkins; Jeffrey Krings; Regina Smith; Leonard Bacharier; James R. Murphy; Douglas Curran-Everett; Patricia Noel

doi:10.1164/rccm.200607-1062OC

Epithelial cell proliferation contributes to airway remodeling in severe asthma

Lance Cohen, E. Xueping, Jaime Tarsi, Thiruvamoor Ramkumar, Todd K. Horiuchi, Rebecca Cochran, Steve DeMartino, Kenneth B. Schechtman, Iftikhar Hussain, Michael J. Holtzman, Mario Castro, Elliot Israel, Bruce D. Levy, Gautham Marigowda, Serpil C. Erzurum, Raed A. Dweik, Suzy A.A. Comhair, Abigail R. Lara, Marcelle Baaklini, Daniel LaskowskiJacqueline Pyle, W. Gerald Teague, Anne M. Fitzpatrick, Eric Hunter, Kian F. Chung, Mark Hew, Alfonso Torrego, Sally Meah, Mun Lim, Sally E. Wenzel, Diane Rhodes, William J. Calhoun, Melissa P. Clark, Renee Folger, Rebecca Z. Wade, Bill T. Ameredes, Dori Smith, Benjamin Gaston, Peter Urban, William W. Busse, Nizar Jarjour, Erin Billmeyer, Cheri Swenson, Gina Crisafi, Eugene R. Bleecker, Deborah Meyers, Wendy Moore, Stephen Peters, Annette Hastie, Gregory Hawkins, Jeffrey Krings, Regina Smith, Leonard Bacharier, James R. Murphy, Douglas Curran-Everett, Patricia Noel

Research output: Contribution to journal › Article › peer-review

204 Scopus citations

Abstract

Rationale: Despite long-term therapy with corticosteroids, patients with severe asthma develop irreversible airway obstruction. Objectives: To evaluate if there are structural and functional differences in the airway epithelium in severe asthma associated with airway remodeling. Methods: In bronchial biopsies from 21 normal subjects, 11 subjects with chronic bronchitis, 9 subjects with mild asthma, and 31 subjects with severe asthma, we evaluated epithelial cell morphology: epithelial thickness, lamina reticularis (LR) thickness, and epithelial desquamation. Levels of retinoblastoma protein (Rb), Ki67, and Bcl-2 were measured, reflecting cellular proliferation and death. Terminal deoxynucleotidyl-mediated dUTP nick end labeling (TUNEL) was used to study cellular apoptosis. Measurements and Main Results: Airway epithelial and LR thickness was greater in subjects with severe asthma compared with those with mild asthma, normal subjects, and diseased control subjects (p = 0.009 and 0.033, respectively). There was no significant difference in epithelial desquamation between groups. Active, hypophosphorylated Rb expression was decreased (p = 0.002) and Ki67 was increased (p < 0.01) in the epithelium of subjects with severe asthma as compared with normal subjects, indicating increased cellular proliferation. Bcl-2 expression was decreased (p < 0.001), indicating decreased cell death suppression. There was a greater level of apoptotic activity in the airway biopsy in subjects with severe asthma as compared with the normal subjects using the TUNEL assay (p = 0.002), suggesting increased cell death. Conclusions: In subjects with severe asthma, as compared with subjects with mild asthma, normal subjects, and diseased control subjects, we found novel evidence of increased cellular proliferation in the airway contributing to a thickened epithelium and LR. These changes may contribute to the progressive decline in lung function and airway remodeling in patients with severe asthma.

Original language	English
Pages (from-to)	138-145
Number of pages	8
Journal	American journal of respiratory and critical care medicine
Volume	176
Issue number	2
DOIs	https://doi.org/10.1164/rccm.200607-1062OC
State	Published - Jul 15 2007

Keywords

Airflow obstruction
Desquamation
Epithelium

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10.1164/rccm.200607-1062OC

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Cohen, L., Xueping, E., Tarsi, J., Ramkumar, T., Horiuchi, T. K., Cochran, R., DeMartino, S., Schechtman, K. B., Hussain, I., Holtzman, M. J., Castro, M., Israel, E., Levy, B. D., Marigowda, G., Erzurum, S. C., Dweik, R. A., Comhair, S. A. A., Lara, A. R., Baaklini, M., ... Noel, P. (2007). Epithelial cell proliferation contributes to airway remodeling in severe asthma. American journal of respiratory and critical care medicine, 176(2), 138-145. https://doi.org/10.1164/rccm.200607-1062OC

@article{c2967c38923a449f8cd9a7ae037075cd,

title = "Epithelial cell proliferation contributes to airway remodeling in severe asthma",

abstract = "Rationale: Despite long-term therapy with corticosteroids, patients with severe asthma develop irreversible airway obstruction. Objectives: To evaluate if there are structural and functional differences in the airway epithelium in severe asthma associated with airway remodeling. Methods: In bronchial biopsies from 21 normal subjects, 11 subjects with chronic bronchitis, 9 subjects with mild asthma, and 31 subjects with severe asthma, we evaluated epithelial cell morphology: epithelial thickness, lamina reticularis (LR) thickness, and epithelial desquamation. Levels of retinoblastoma protein (Rb), Ki67, and Bcl-2 were measured, reflecting cellular proliferation and death. Terminal deoxynucleotidyl-mediated dUTP nick end labeling (TUNEL) was used to study cellular apoptosis. Measurements and Main Results: Airway epithelial and LR thickness was greater in subjects with severe asthma compared with those with mild asthma, normal subjects, and diseased control subjects (p = 0.009 and 0.033, respectively). There was no significant difference in epithelial desquamation between groups. Active, hypophosphorylated Rb expression was decreased (p = 0.002) and Ki67 was increased (p < 0.01) in the epithelium of subjects with severe asthma as compared with normal subjects, indicating increased cellular proliferation. Bcl-2 expression was decreased (p < 0.001), indicating decreased cell death suppression. There was a greater level of apoptotic activity in the airway biopsy in subjects with severe asthma as compared with the normal subjects using the TUNEL assay (p = 0.002), suggesting increased cell death. Conclusions: In subjects with severe asthma, as compared with subjects with mild asthma, normal subjects, and diseased control subjects, we found novel evidence of increased cellular proliferation in the airway contributing to a thickened epithelium and LR. These changes may contribute to the progressive decline in lung function and airway remodeling in patients with severe asthma.",

keywords = "Airflow obstruction, Desquamation, Epithelium",

author = "Lance Cohen and E. Xueping and Jaime Tarsi and Thiruvamoor Ramkumar and Horiuchi, {Todd K.} and Rebecca Cochran and Steve DeMartino and Schechtman, {Kenneth B.} and Iftikhar Hussain and Holtzman, {Michael J.} and Mario Castro and Elliot Israel and Levy, {Bruce D.} and Gautham Marigowda and Erzurum, {Serpil C.} and Dweik, {Raed A.} and Comhair, {Suzy A.A.} and Lara, {Abigail R.} and Marcelle Baaklini and Daniel Laskowski and Jacqueline Pyle and Teague, {W. Gerald} and Fitzpatrick, {Anne M.} and Eric Hunter and Chung, {Kian F.} and Mark Hew and Alfonso Torrego and Sally Meah and Mun Lim and Wenzel, {Sally E.} and Diane Rhodes and Calhoun, {William J.} and Clark, {Melissa P.} and Renee Folger and Wade, {Rebecca Z.} and Ameredes, {Bill T.} and Dori Smith and Benjamin Gaston and Peter Urban and Busse, {William W.} and Nizar Jarjour and Erin Billmeyer and Cheri Swenson and Gina Crisafi and Bleecker, {Eugene R.} and Deborah Meyers and Wendy Moore and Stephen Peters and Annette Hastie and Gregory Hawkins and Jeffrey Krings and Regina Smith and Leonard Bacharier and Murphy, {James R.} and Douglas Curran-Everett and Patricia Noel",

year = "2007",

month = jul,

day = "15",

doi = "10.1164/rccm.200607-1062OC",

language = "English",

volume = "176",

pages = "138--145",

journal = "American journal of respiratory and critical care medicine",

issn = "1073-449X",

number = "2",

}

Cohen, L, Xueping, E, Tarsi, J, Ramkumar, T, Horiuchi, TK, Cochran, R, DeMartino, S, Schechtman, KB, Hussain, I, Holtzman, MJ, Castro, M, Israel, E, Levy, BD, Marigowda, G, Erzurum, SC, Dweik, RA, Comhair, SAA, Lara, AR, Baaklini, M, Laskowski, D, Pyle, J, Teague, WG, Fitzpatrick, AM, Hunter, E, Chung, KF, Hew, M, Torrego, A, Meah, S, Lim, M, Wenzel, SE, Rhodes, D, Calhoun, WJ, Clark, MP, Folger, R, Wade, RZ, Ameredes, BT, Smith, D, Gaston, B, Urban, P, Busse, WW, Jarjour, N, Billmeyer, E, Swenson, C, Crisafi, G, Bleecker, ER, Meyers, D, Moore, W, Peters, S, Hastie, A, Hawkins, G, Krings, J, Smith, R, Bacharier, L, Murphy, JR, Curran-Everett, D & Noel, P 2007, 'Epithelial cell proliferation contributes to airway remodeling in severe asthma', American journal of respiratory and critical care medicine, vol. 176, no. 2, pp. 138-145. https://doi.org/10.1164/rccm.200607-1062OC

TY - JOUR

T1 - Epithelial cell proliferation contributes to airway remodeling in severe asthma

AU - Cohen, Lance

AU - Xueping, E.

AU - Tarsi, Jaime

AU - Ramkumar, Thiruvamoor

AU - Horiuchi, Todd K.

AU - Cochran, Rebecca

AU - DeMartino, Steve

AU - Schechtman, Kenneth B.

AU - Hussain, Iftikhar

AU - Holtzman, Michael J.

AU - Castro, Mario

AU - Israel, Elliot

AU - Levy, Bruce D.

AU - Marigowda, Gautham

AU - Erzurum, Serpil C.

AU - Dweik, Raed A.

AU - Comhair, Suzy A.A.

AU - Lara, Abigail R.

AU - Baaklini, Marcelle

AU - Laskowski, Daniel

AU - Pyle, Jacqueline

AU - Teague, W. Gerald

AU - Fitzpatrick, Anne M.

AU - Hunter, Eric

AU - Chung, Kian F.

AU - Hew, Mark

AU - Torrego, Alfonso

AU - Meah, Sally

AU - Lim, Mun

AU - Wenzel, Sally E.

AU - Rhodes, Diane

AU - Calhoun, William J.

AU - Clark, Melissa P.

AU - Folger, Renee

AU - Wade, Rebecca Z.

AU - Ameredes, Bill T.

AU - Smith, Dori

AU - Gaston, Benjamin

AU - Urban, Peter

AU - Busse, William W.

AU - Jarjour, Nizar

AU - Billmeyer, Erin

AU - Swenson, Cheri

AU - Crisafi, Gina

AU - Bleecker, Eugene R.

AU - Meyers, Deborah

AU - Moore, Wendy

AU - Peters, Stephen

AU - Hastie, Annette

AU - Hawkins, Gregory

AU - Krings, Jeffrey

AU - Smith, Regina

AU - Bacharier, Leonard

AU - Murphy, James R.

AU - Curran-Everett, Douglas

AU - Noel, Patricia

PY - 2007/7/15

Y1 - 2007/7/15

N2 - Rationale: Despite long-term therapy with corticosteroids, patients with severe asthma develop irreversible airway obstruction. Objectives: To evaluate if there are structural and functional differences in the airway epithelium in severe asthma associated with airway remodeling. Methods: In bronchial biopsies from 21 normal subjects, 11 subjects with chronic bronchitis, 9 subjects with mild asthma, and 31 subjects with severe asthma, we evaluated epithelial cell morphology: epithelial thickness, lamina reticularis (LR) thickness, and epithelial desquamation. Levels of retinoblastoma protein (Rb), Ki67, and Bcl-2 were measured, reflecting cellular proliferation and death. Terminal deoxynucleotidyl-mediated dUTP nick end labeling (TUNEL) was used to study cellular apoptosis. Measurements and Main Results: Airway epithelial and LR thickness was greater in subjects with severe asthma compared with those with mild asthma, normal subjects, and diseased control subjects (p = 0.009 and 0.033, respectively). There was no significant difference in epithelial desquamation between groups. Active, hypophosphorylated Rb expression was decreased (p = 0.002) and Ki67 was increased (p < 0.01) in the epithelium of subjects with severe asthma as compared with normal subjects, indicating increased cellular proliferation. Bcl-2 expression was decreased (p < 0.001), indicating decreased cell death suppression. There was a greater level of apoptotic activity in the airway biopsy in subjects with severe asthma as compared with the normal subjects using the TUNEL assay (p = 0.002), suggesting increased cell death. Conclusions: In subjects with severe asthma, as compared with subjects with mild asthma, normal subjects, and diseased control subjects, we found novel evidence of increased cellular proliferation in the airway contributing to a thickened epithelium and LR. These changes may contribute to the progressive decline in lung function and airway remodeling in patients with severe asthma.

AB - Rationale: Despite long-term therapy with corticosteroids, patients with severe asthma develop irreversible airway obstruction. Objectives: To evaluate if there are structural and functional differences in the airway epithelium in severe asthma associated with airway remodeling. Methods: In bronchial biopsies from 21 normal subjects, 11 subjects with chronic bronchitis, 9 subjects with mild asthma, and 31 subjects with severe asthma, we evaluated epithelial cell morphology: epithelial thickness, lamina reticularis (LR) thickness, and epithelial desquamation. Levels of retinoblastoma protein (Rb), Ki67, and Bcl-2 were measured, reflecting cellular proliferation and death. Terminal deoxynucleotidyl-mediated dUTP nick end labeling (TUNEL) was used to study cellular apoptosis. Measurements and Main Results: Airway epithelial and LR thickness was greater in subjects with severe asthma compared with those with mild asthma, normal subjects, and diseased control subjects (p = 0.009 and 0.033, respectively). There was no significant difference in epithelial desquamation between groups. Active, hypophosphorylated Rb expression was decreased (p = 0.002) and Ki67 was increased (p < 0.01) in the epithelium of subjects with severe asthma as compared with normal subjects, indicating increased cellular proliferation. Bcl-2 expression was decreased (p < 0.001), indicating decreased cell death suppression. There was a greater level of apoptotic activity in the airway biopsy in subjects with severe asthma as compared with the normal subjects using the TUNEL assay (p = 0.002), suggesting increased cell death. Conclusions: In subjects with severe asthma, as compared with subjects with mild asthma, normal subjects, and diseased control subjects, we found novel evidence of increased cellular proliferation in the airway contributing to a thickened epithelium and LR. These changes may contribute to the progressive decline in lung function and airway remodeling in patients with severe asthma.

KW - Airflow obstruction

KW - Desquamation

KW - Epithelium

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U2 - 10.1164/rccm.200607-1062OC

DO - 10.1164/rccm.200607-1062OC

M3 - Article

C2 - 17463414

AN - SCOPUS:34447318645

SN - 1073-449X

VL - 176

SP - 138

EP - 145

JO - American journal of respiratory and critical care medicine

JF - American journal of respiratory and critical care medicine

IS - 2

ER -

Epithelial cell proliferation contributes to airway remodeling in severe asthma

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Keywords

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