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 Calhoun, Melissa P. Clark, Renee Folger, Rebecca Z. Wade, Bill 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 journalArticle

149 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)138-145
Number of pages8
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume176
Issue number2
DOIs
StatePublished - Jul 15 2007

Fingerprint

Airway Remodeling
Asthma
Epithelial Cells
Cell Proliferation
Epithelium
Cell Death
Biopsy
Retinoblastoma Protein
Chronic Bronchitis
Airway Obstruction
Adrenal Cortex Hormones

Keywords

  • Airflow obstruction
  • Desquamation
  • Epithelium

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Cohen, L., Xueping, E., Tarsi, J., Ramkumar, T., Horiuchi, T. K., Cochran, R., ... 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

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

In: American Journal of Respiratory and Critical Care Medicine, Vol. 176, No. 2, 15.07.2007, p. 138-145.

Research output: Contribution to journalArticle

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, W, Clark, MP, Folger, R, Wade, RZ, Ameredes, B, 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
Cohen, Lance ; Xueping, E. ; Tarsi, Jaime ; Ramkumar, Thiruvamoor ; Horiuchi, Todd K. ; Cochran, Rebecca ; DeMartino, Steve ; Schechtman, Kenneth B. ; Hussain, Iftikhar ; Holtzman, Michael J. ; Castro, Mario ; Israel, Elliot ; Levy, Bruce D. ; Marigowda, Gautham ; Erzurum, Serpil C. ; Dweik, Raed A. ; Comhair, Suzy A A ; Lara, Abigail R. ; Baaklini, Marcelle ; Laskowski, Daniel ; Pyle, Jacqueline ; Teague, W. Gerald ; Fitzpatrick, Anne M. ; Hunter, Eric ; Chung, Kian F. ; Hew, Mark ; Torrego, Alfonso ; Meah, Sally ; Lim, Mun ; Wenzel, Sally E. ; Rhodes, Diane ; Calhoun, William ; Clark, Melissa P. ; Folger, Renee ; Wade, Rebecca Z. ; Ameredes, Bill ; Smith, Dori ; Gaston, Benjamin ; Urban, Peter ; Busse, William W. ; Jarjour, Nizar ; Billmeyer, Erin ; Swenson, Cheri ; Crisafi, Gina ; Bleecker, Eugene R. ; Meyers, Deborah ; Moore, Wendy ; Peters, Stephen ; Hastie, Annette ; Hawkins, Gregory ; Krings, Jeffrey ; Smith, Regina ; Bacharier, Leonard ; Murphy, James R. ; Curran-Everett, Douglas ; Noel, Patricia. / Epithelial cell proliferation contributes to airway remodeling in severe asthma. In: American Journal of Respiratory and Critical Care Medicine. 2007 ; Vol. 176, No. 2. pp. 138-145.
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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.",
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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

AU - Clark, Melissa P.

AU - Folger, Renee

AU - Wade, Rebecca Z.

AU - Ameredes, Bill

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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