Acute Respiratory Distress Syndrome (ARDS) causes significant morbidity and mortality each year. There is a paucity of information regarding the mechanisms necessary for ARDS resolution. Foxp3+ regulatory T cells (Tregs) have been shown to be an important determinant of resolution in an experimental model of lung injury. We demonstrate that intratracheal delivery of endotoxin (LPS) elicits alveolar epithelial damage from which the epithelium undergoes proliferation and repair. Epithelial proliferation coincided with an increase in Foxp3+ Treg cells in the lung during the course of resolution. To dissect the role that Foxp3+ Treg cells exert on epithelial proliferation, we depleted Foxp3+ Treg cells which led to decreased alveolar epithelial proliferation and delayed lung injury recovery. Furthermore, antibody-mediated blockade of CD103, an integrin, which binds to epithelial expressed E-cadherin decreased Foxp3+ Treg numbers and decreased rates of epithelial proliferation after injury. In a non-inflammatory model of regenerative alveologenesis, left lung pneumonectomy (PNX), we found that Foxp3+ Treg cells enhanced epithelial proliferation. Moreover, Foxp3+ Treg cells co-cultured with primary type II alveolar cells (AT2) directly increased AT2 cell proliferation in a CD103-dependent manner. These studies provide evidence of a new and integral role for Foxp3+ Treg cells in repair of the lung epithelium.
Acute lung injury (ALI) causes significant morbidity and mortality. Fibroproliferation in ALI results in worse outcomes, but the mechanisms governing fibroproliferation remain poorly understood. Regulatory T cells (Tregs) are important in lung injury resolution. Their role in fibroproliferation is unknown. We sought to identify the role of Tregs in ALI fibroproliferation, using a murine model of lung injury. Wild-type (WT) and lymphocyte-deficient Rag-1 2/2 mice received intratracheal LPS. Fibroproliferation was characterized by histology and the measurement of lung collagen. Lung fibrocytes were measured by flow cytometry. To dissect the role of Tregs in fibroproliferation, Rag-1 2/2 mice received CD4 1 CD25 1 (Tregs) or CD4 1 CD252 Tcells (non-Tregs) at the time of LPS injury. To define the role of the chemokine (C-X-C motif) ligand 12 (CXCL12)-CXCR4 pathway in ALI fibroproliferation, Rag-1 2/2 mice were treated with the CXCR4 antagonist AMD3100 to block fibrocyte recruitment. WT and Rag-1 2/2 mice demonstrated significant collagen deposition on Day 3 after LPS. WT mice exhibited the clearance of collagen, but Rag-1 2/2 mice developed persistent fibrosis. This fibrosis was mediated by the sustained epithelial expression of CXCL12 (or stromal cell-derived factor 1 [SDF-1]) that led to increased fibrocyte recruitment. The adoptive transfer of Tregs resolved fibroproliferation by decreasing CXCL12 expression and subsequent fibrocyte recruitment. Blockade of the CXCL12-CXCR4 axis with AMD3100 also decreased lung fibrocytes and fibroproliferation. These results indicate a central role for Tregs in the resolution of ALI fibroproliferation by reducing fibrocyte recruitment along the CXCL12-CXCR4 axis. A dissection of the role of Tregs in ALI fibroproliferation may inform the design of new therapeutic tools for patients with ALI.Keywords: acute lung injury; fibroproliferative ARDS; fibrocytes; regulatory T cells; lung injury resolution Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) affect 190,000 individuals in the United States each year, accounting for 75,000 deaths (1). The only treatment that improves outcomes involves a lung-protective strategy in patients on mechanical ventilation (2). Mortality from ALI/ARDS remains as high as 44% (3).ALI/ARDS is divided into an exudative phase marked by edema fluid, hyaline membrane formation, and neutrophilic infiltration, followed in some patients by a fibroproliferative phase (4). Fibroproliferation is part of the normal repair response, and is characterized by the intra-alveolar accumulation of fibroblasts and collagen deposition. If this process is ineffective or continues unabated, patients may develop fibrosis (5). Longer durations of ARDS correspond to increased lung collagen and fibrosis, and portend worse outcomes (6). Fibroproliferative changes on biopsy and computed tomography predict mortality (7,8). The determinants of prolonged fibroproliferation and factors that govern its resolution remain poorly understood.The fibroblast is a key cell ...
The pulmonary epithelium serves as a barrier to prevent access of the inspired luminal contents to the subepithelium. In addition, the epithelium dictates the initial responses of the lung to both infectious and noninfectious stimuli. One mechanism by which the epithelium does this is by coordinating transport of diffusible molecules across the epithelial barrier, both through the cell and between cells. In this review, we will discuss a few emerging paradigms of permeability changes through altered ion transport and paracellular regulation by which the epithelium gates its response to potentially detrimental luminal stimuli. This review is a summary of talks presented during a symposium in Experimental Biology geared toward novel and less recognized methods of epithelial barrier regulation. First, we will discuss mechanisms of dynamic regulation of cell-cell contacts in the context of repetitive exposure to inhaled infectious and noninfectious insults. In the second section, we will briefly discuss mechanisms of transcellular ion homeostasis specifically focused on the role of claudins and paracellular ion-channel regulation in chronic barrier dysfunction. In the next section, we will address transcellular ion transport and highlight the role of Trek-1 in epithelial responses to lung injury. In the final section, we will outline the role of epithelial growth receptor in barrier regulation in baseline, acute lung injury, and airway disease. We will then end with a summary of mechanisms of epithelial control as well as discuss emerging paradigms of the epithelium role in shifting between a structural element that maintains tight cell-cell adhesion to a cell that initiates and participates in immune responses.
As the interface with the outside world, the airway epithelial barrier is critical to lung defense. Because of respiratory efforts, the airways are exposed to shear stress; however, little is known regarding the effects of shear on epithelial function. We report that low-level shear stress enhances epithelial barrier function, an effect that requires serial activation of the transient receptor potential vanilloid (TRPV) 4 and L-type voltage-gated calcium channel (VGCC) and an increase in intracellular calcium. These changes lead to a selective decrease in aquaporin-5 (AQP5) abundance because of protein internalization and degradation. To determine whether AQP5 plays a role in mediating the shear effects on paracellular permeability, we overexpressed hAQP5 in 16HBE cells, an airway epithelial cell line without endogenous AQP5. We found that AQP5 expression was needed for shearinduced barrier enhancement. These findings have direct relevance to the regulation of epithelial barrier function, membrane permeability, and water homeostasis in the respiratory epithelia.permeability ͉ epithelium ͉ transient receptor potential vanilloid ͉ voltage-gated calcium channel ͉ cytoskeleton M echanical forces elicit biologically relevant signals, best demonstrated in the cardiovascular and musculoskeletal systems, where stretch and shear alter differentiation and proliferation (1-5). The airway wall exists in a mechanically dynamic environment, and each breath causes circumferential and longitudinal expansion and contraction (6). Airway epithelial cells are exposed to luminal shear stress (frictional force per surface area) generated by airflow, which at rest breathing is 0.5-3 dynes/cm 2 . Shear forces may be a log higher with exercise (7, 8) and may increase to nearly 1,700 dynes/cm 2 with cough and bronchospasm (8). In asthma, smooth muscle constriction produces airway folding, reducing luminal caliber producing heterogeneous shear at different parts along the airway (9).Endothelial shear stress alters cytoskeletal organization, cell shape, and gene expression (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Endothelial shear increases intracellular calcium concentration [Ca 2ϩ ] i , triggering nitric oxide production (20), changes in actin stress fiber formation, and altered paracellular permeability (21) in part due to activation of transient receptor potential vanilloid (TRPV) 4, a nonselective cation channel (22). Mechanical stimulation alters airway epithelial EGF signaling (23), surface liquid height (8), and ciliary beat frequency (24). TRPV4 is also present in airway epithelial cells and is activated by temperature, hypotonicity (25-28), and shear stress (22,(29)(30)(31). TRPV4 activation has been implicated in alveolar septal barrier function (32), but its role in airway epithelia remains undefined.We find that low levels of shear stress enhance airway epithelial barrier function, an effect mediated through increases in [Ca 2ϩ ] i by sequential activation of TRPV4 and voltage-gated calcium channel (VGCC). Although VGC...
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