b-Arrestins in the Immune System - Progress in Molecular Biology and Translational Science - page 368

Epithelial cell Inflammatory cell Fibroblast/myofibroblast

Angiotensin II Chemokine Cytokine TGF β LPA Ligand

Angiotensin
receptor

Receptor Cytokine

receptor

TGF β LPAR1 ? Receptor

receptor

Arrestin Arrestin Arrestin Arrestin Arrestin Arrestin

Epithelial cell
apoptosis

Chemotaxis
Cytokine release

Chemotaxis
Cytokine release

Migration Invasion

Excessive
matrix production
Loss of integrity

Epithelial cell
injury

Fibroblast activation
Myofibroblast differentiation

Dysregulated inflammation

Insults

Figure 14.2 b-Arrestins mediate signaling pathways during fibrogenesis. A simplified
model of tissue fibrosis proposes that epithelial cell injury and apoptosis lead to dys-
regulated inflammatory responses and fibroblast/myofibroblast activation, resulting
in excessive matrix production and eventually fibrosis. b-Arrestins regulate signaling
pathways mediating cell injury and apoptosis in epithelial cells, inflammatory responses
in immune cells, and fibroblast migration and invasiveness, matrix production in effec-
tor cells.

Fibroblast and myofibroblast migration is an important process during
fibrogenesis. Chemokines and chemokine receptors regulate fibroblast
migration. 145,146 Furthermore, lysophosphatidic acid in bronchoalveolar
lavage fluid interacts with its receptor LPAR1, regulating fibroblast migra-
tion during fibrogenesis. 147 b -Arrestins regulate chemokine signaling as well

as LPAR1 signaling. The role of b -arrestins in fibroblast migration has not
been explored. We have shown that deletion of b -arrestins did not signif-
icantly affect fibroblast migration. 131
The destruction of alveolar basement membrane was observed in exper-
imental lung fibrosis and the biopsies of patients with lung fibrosis. 148 More-
over, fibroblasts and myofibroblasts from patients with progressive lung
fibrosis have been shown to have the ability to invade extracellular matrix
in the manner of metastatic cancer cells. 148 b -Arrestins have been shown

to play a role in tumor metastasis. 16,17 For example, b -arrestin signaling
mediates

lysophosphatidic acid-induced cancer cell migration and