Mechanisms of murine lacrimal gland repair following experimentally induced inflammation
Driss Zoukhri 1*,
Amanda Fix 2,
Joseph Alroy 3,
and
Claire L Kublin 2
1 General Dentistry, Tufts University School of Dental Medicine, DHS 834, Boston, Massachusetts, 02111, United States; Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts, United States
2 General Dentistry, Tufts University School of Dental Medicine, Boston, Massachusetts, United States
3 Department of Pathology, Tufts University School of Medicine, Boston, Massachusetts, United States; Cummings School of Veterinary Medicine and Tufts-New England Medical Center, Boston, Massachusetts, United States
* To whom correspondence should be addressed. E-mail: driss.zoukhri{at}tufts.edu.
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Abstract |
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Purpose. We recently reported that a severe inflammatory response that resulted in substantial loss of acinar cells was induced by a single injection of interleukin-1 a into the lacrimal gland and that this effect was reversible. The purpose of the present study was to determine the mechanisms involved in lacrimal gland injury and repair. Methods. Inflammation was induced by direct injection of recombinant human interleukin-1
(IL-1, 1 µg in 2 µl) into the exorbital lacrimal glands of anesthetized female BALB/c mice. Animals were sacrificed 1, 2, 3, 4, 5, 6, or 7 days following the injection. The exorbital lacrimal glands were then removed and processed for measurement of protein secretion, histology, immunohistochemistry and western blotting.
Results. Our results show that lacrimal gland acinar cells are lost through programmed cell death through apoptosis and autophagy. They also show that the number of nestin (a stem cell marker) positive cells increased 2-3 day following injury and that some of these cells are also positive for Ki67 (a cell proliferation marker) and -smooth muscle actin (a marker of myoepithelial cells). Finally, we show that the amount of phosphorylated Smad1/5/8 (effector molecules of bone morphogenetic protein 7, BMP7) increases 2-3 days following injury and can also be detected in nestin-positive cells.
Conclusions. We conclude from these studies that the lacrimal gland contains stem/progenitor cells that are capable of tissue repair following injury. We hypothesize that programmed cell death following injury triggers proliferation and differentiation of these cells, presumably through activation of the BMP7 pathway.
Key Words:
apoptosis, lacrimal gland, interleukin, autoimmune response/disease, dry eyes, epithelial cells
