Acute lung Injury (ALI) and the more severe Acute Respiratory Distress Syndrome (ARDS) are diffuse lung diseases that cause tremendous morbidity and mortality in the United States each year. Despite decades of research into the pathogenesis and mechanisms underlying the development of ARDS, mortality remains high and the only treatment shown to be effective is low tidal volume ventilation in patients who require ventilatory support. A subset of patients with ARDS progress to a fibroproliferative stage marked pathologically by fibrosis and clinically by increasing dead space, decreasing lung compliance and worsening oxygenation. Recent interest has shifted from the factors that promote the development of ALI to determinants of the resolution of lung injury. Regulatory T cells (Tregs) have been found to be critical to the resolution of ALI in a mouse model of LPS-induced lung injury. They have also been shown to increase in number in the BAL fluid of patients with ARDS, suggesting that they likely play an important role in the normal human response to ALI. The role of Tregs in the fibroproliferative response to ALI has not been studied. The goal of this proposal is to determine the role of Tregs in the fibroproliferative response to ALI, with the hope of identifying novel mechanisms that may ultimately lead to future treatment options in patients with ALI. In order to achieve this goal this proposal will utilize both in vivo and in vitro techniques to examine the role of Tregs in fibroproliferation after LPS-induced ALI. For the in vivo arm, C57BL/6 wildtype (WT) mice and Rag-1-/- lymphocyte deficient mice will be exposed to intratracheal (i.t.) LPS and the resulting fibroproliferative response will be rigorously phenotyped. Adoptive transfer of Tregs into Rag-1-/- mice will be employed to examine the specific effects of Tregs on the fibroproliferative response. In the in vitro experiments, fibroblasts will be grown in cell culture under various stimulating conditions. Tregs and macrophages will be added in different co-culture combinations to examine the cellular mechanisms by which Tregs modify fibroblast function. These experiments will explore new observations on the role of Tregs in the fibroproliferative response to ALI with the ultimate goal of improving patient outcomes in this oftentimes fatal disease.

Public Health Relevance

Acute lung injury (ALI) is a common and oftentimes fatal pulmonary disease that may result in lung fibrosis. T- regulatory (Treg) cells have been shown to be important in the resolution of ALI but their role in the development of fibrosis after ALI is unknown. We propose to study the effect of Tregs on the fibroproliferative response to ALI with the hope of identifying novel mechanisms that may ultimately lead to new therapeutic options for this disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F10A-S (20))
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Colombini-Hatch, Sandra
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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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Garibaldi, Brian T; D'Alessio, Franco R; Mock, Jason R et al. (2013) Regulatory T cells reduce acute lung injury fibroproliferation by decreasing fibrocyte recruitment. Am J Respir Cell Mol Biol 48:35-43