Regional fibroblast heterogeneity in the lung: implications for remodeling.
BACKGROUND
Excessive deposition of extracellular matrix occurs in proximal airways of individuals with asthma, but fibrosis in distal lung has not been observed. Whether differing fibrotic capacities of fibroblasts from these two regions contribute to this variability is unknown.


OBJECTIVE
We compared morphologic and functional characteristics of fibroblasts isolated from proximal airways and distal lung parenchyma to determine phenotypic differences.


METHODS
Concurrent proximal airway and distal lung biopsies were obtained by bronchoscopy from subjects with asthma to isolate airway and distal lung fibroblasts, respectively. The following characteristics were compared: morphology, proliferation, alpha-smooth muscle actin expression, and synthesis of procollagen type I and eotaxin-1.


RESULTS
Airway fibroblasts (AFs) are morphologically distinct from distal lung fibroblasts (DLFs): they are larger (2.3-fold greater surface area vs. matched DLFs; p = 0.02), stellate in appearance, and with more cytoplasmic projections compared with the spindle-shaped DLFs. AFs synthesized more procollagen type I than did DLFs at baseline (twofold higher; p = 0.003) and after transforming growth factor-beta stimulation (1.4-fold higher; p = 0.02). Similarly, AFs produced more eotaxin-1 than did DLFs at baseline (2.5-fold higher; p = 0.004) and after interleukin-13 stimulation (13-fold higher; p = 0.0001). In contrast, DLFs proliferate more than AFs with serum stimulation (about sixfold greater; p = 0.03). Unstimulated DLFs also expressed more alpha-smooth muscle actin than did corresponding AFs (p = 0.006).


CONCLUSIONS
These studies suggest that at least two phenotypes of fibroblast exist in the lung. These phenotypic differences may partially explain the variable responses to injury and repair between proximal airways and distal lung/parenchyma in asthma and other respiratory diseases.
Kotaru
Chakradhar
C
National Jewish Medical and Research Center and University of Colorado Health Sciences Center, Denver, CO 80206, USA. kotaruc@njc.org
Schoonover
Kathryn J
KJ
Trudeau
John B
JB
Huynh
Mai-Lan
ML
Zhou
XiuXia
X
Hu
Haizhen
H
Wenzel
Sally E
SE
D000199:Actins / Q000187:drug effects / Q000378:metabolism; D000328:Adult; D001249:Asthma / Q000473:pathology*; D001980:Bronchi / Q000166:cytology*; D049109:Cell Proliferation; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000096:biosynthesis; D024042:Collagen Type I / Q000096:biosynthesis; D005109:Extracellular Matrix / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000166:cytology*; D006801:Humans; D008168:Lung / Q000166:cytology*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D000199:Actins; C515456:CCL11 protein, human; D054413:Chemokine CCL11; D019742:Chemokines, CC; D024042:Collagen Type I; D016212:Transforming Growth Factor beta