Elizabeth Pierce
e-mail address: empierce@umich.edu

Mentor: Cory Hogaboam, PhD

Research Description

Usual Interstitial Pneumonia (UIP) and non-specific interstitial
pneumonia (NSIP) are among the more severe forms of Idiopathic
Interstitial Pneumonia, (IIP). Since surgical lung biopsies (SLBs)
from IIP patients exhibit focal expression of CCR7, we examined the
functional significance of CCR7 expression and the effect of its
ligands on signaling in primary fibroblasts grown from IIP and normal
SLBs. To further study the role of CCR7 in IIP, we developed a murine
SCID model, into which we introduced these primary fibroblast lines.
The greatest CCR7 expression was detected in primary fibroblasts from
UIP patients relative to NSIP and normal patients. When treated with
CCL21, UIP, but not NSIP or normal, fibroblasts showed a migratory
phenotype dependant on functional CCR7. Conversely, CCL21 promoted
proliferation in UIP and NSIP, but not normal, fibroblasts. Fibroblast
lysates were Western blotted for the phosphorylation status of ERK,
which has been shown to be involved in cell migration, cell
proliferation and tissue remodeling. UIP, but not NSIP or normal,
fibroblasts exhibited increased ERK pathway phophorylation when treated
with CCL21, and was blocked when pretreated with pertussis toxin or
CCR7 siRNA. Intravenous injection of UIP fibroblasts into CB-17 SCID/bg
mic led to fibroblastic foci and interstitial fibrosis at day 63
post-injection. In contrast, mice that received normal human
fibroblasts via the same route did not exhibit these histological
changes. Mice that received UIP fibroblasts showed significantly higher
whole lung levels of CCL21 protein compared to mice that received
normal fibroblasts. Immunoneutralization of CCR7 or CCL21 attenuated
the magnitude of fibrosis and reduced whole lung levels of CCL21 in
mice that received UIP fibroblasts. Taken together, these data
demonstrate that CCL21 modulates the functional properties of IIP and
that CCR7 is necessary for the maintenance of fibrosis in the mouse
model.

Publications

Neel NF, Creasy BM, Rankin JN, Pierce EM, McCoy ME, Daner RH, Fowler
JA, Daniel JC, Lantz CS. Absence of interleukin-3 does not affect the
severity of local and systemic anaphylaxis but does enhance eosinophil
infiltration in a mouse model of allergic peritonitis. Immunol Lett.
2004 Aug 15;95(1):37-44.

Choi ES, Pierce EM, Jakubzick C, Carpenter KJ, Kunkel SL, Evanoff H,
Martinez FJ, Flaherty KR, Moore BB, Toews GB, Colby TV, Kazerooni EA,
Gross BH, Travis WD, Hogaboam CM. Focal interstitial CC chemokine
receptor 7 (CCR7) expression in idiopathic interstitial pneumonia. J
Clin Pathol. 2006 Jan;59(1):28-39.

Pierce EM, Carpenter KJ, Jakubzick C, Kunkel SL, Martinez FJ, Flaherty
KR, Hogaboam CM. Therapeutic Targeting of CCL21 or CCR7 Abrogates
Pulmonary Fibrosis Induced by the Adoptive Transfer of Human Pulmonary
Fibroblasts to Immunodeficient Mice. Submitted to The American Journal
of Pathology.

Pierce EM, Carpenter KJ, Jakubzick C, Kunkel SL, Evanoff H, Flaherty
KR, Martinez FJ, Toews GB, Hogaboam CM. Idiopathic Pulmonary Fibrosis
Fibroblasts Migrate and Proliferate to CC Chemokine Receptor-7 Ligands.
Manuscript in preparation.

Abstracts

Pierce, EM, Carpenter, K, Jakubzick, CJ, Kunkel, SL, Flaherty, KR,
Martinez, FJ, Hogaboam, CM. A Novel Murine Model of Human IIP. ATS meeting, May, 2004.

Elizabeth M Pierce, Carpenter K, Jakubzick C, Kunkel SL, Flaherty KR,
Martinez FJ, Toews GB, Hogaboam CM. CCL21 Induces Phosphorylation of
ERK in Usual Interstitial Pneumonia Fibroblasts. 2006 AAI Annual
Meeting, May 2006.