Changes in Collagen Turnover in Early Acute Respiratory  Distress Syndrome

Armstrong, Lynne; Thickett, David; Mansell, JP; Ionescu, Mirela; Hoyle, Eric; Billinghurst, R. Clark; Poole, A. Robin; Millar, Ann

doi:10.1164/ajrccm.160.6.9811084

Cited by 64 publications

(53 citation statements)

References 19 publications

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“…Some experimental studies corroborate this early onset of collagen deposition [3]. Moreover, patients show an increase in procollagen levels in the fi rst 48 hours after meeting ALI criteria [4].…”

Section: An Overview Of the Repair Processmentioning

confidence: 77%

Repair after Acute Lung Injury: Molecular Mechanisms and Therapeutic Opportunities

González-López¹,

Albaiceta²

2012

Annual Update in Intensive Care and Emergency Medicine 2012

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Section: An Overview Of the Repair Processmentioning

confidence: 77%

Repair after Acute Lung Injury: Molecular Mechanisms and Therapeutic Opportunities

González-López¹,

Albaiceta²

2012

Annual Update in Intensive Care and Emergency Medicine 2012

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“…This repair begins early, as evidenced by increased markers of collagen turnover in the BAL fluid of patients with ARDS within the first days of diagnosis (25,26). However, excessive fibroproliferation is associated with worse outcomes, because patients develop decreased lung compliance and increased dead space, and require prolonged mechanical ventilation (4,6,8).…”

Section: Discussionmentioning

confidence: 99%

Regulatory T Cells Reduce Acute Lung Injury Fibroproliferation by Decreasing Fibrocyte Recruitment

Garibaldi

D’Alessio

Mock

et al. 2013

Am J Respir Cell Mol Biol

155

135

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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 ...

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“…One study of patients with ARDS and acute lung injury measured the ratio of the COOH-terminal propeptide of type I collagen (a marker of collagen synthesis) to the carboxy terminal sequence of the 3/4 degradation fragment of type I collagen (a marker of collagen degradation). The authors found that patients with more severe lung injury had less total and relative quantities of degraded collagen fragments and higher levels of collagen propeptide, indicating an in vivo defect in collagen degradation (1). Taken together, these data suggest that in areas of fibrosis there is inhibition of the pathways that mediate extracellular collagen degradation.…”

Section: Consequences Of Impaired Extra-or Intracellular Degradation mentioning

confidence: 93%

Always cleave up your mess: targeting collagen degradation to treat tissue fibrosis

McKleroy

Lee

Atabai

2013

American Journal of Physiology-Lung Cellular and Molecular Phys

211

169

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Pulmonary fibrosis is a vexing clinical problem with no proven therapeutic options. In the normal lung there is continuous collagen synthesis and collagen degradation, and these two processes are precisely balanced to maintain normal tissue architecture. With lung injury there is an increase in the rate of both collagen production and collagen degradation. The increase in collagen degradation is critical in preventing the formation of permanent scar tissue each time the lung is exposed to injury. In pulmonary fibrosis, collagen degradation does not keep pace with collagen production, resulting in extracellular accumulation of fibrillar collagen. Collagen degradation occurs through both extracellular and intracellular pathways. The extracellular pathway involves cleavage of collagen fibrils by proteolytic enzyme including the metalloproteinases. The less-well-described intracellular pathway involves binding and uptake of collagen fragments by fibroblasts and macrophages for lysosomal degradation. The relationship between these two pathways and their relevance to the development of fibrosis is complex. Fibrosis in the lung, liver, and skin has been associated with an impaired degradative environment. Much of the current scientific effort in fibrosis is focused on understanding the pathways that regulate increased collagen production. However, recent reports suggest an important role for collagen turnover and degradation in regulating the severity of tissue fibrosis. The objective of this review is to evaluate the roles of the extracellular and intracellular collagen degradation pathways in the development of fibrosis and to examine whether pulmonary fibrosis can be viewed as a disease of impaired matrix degradation rather than a disease of increased matrix production.

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Changes in Collagen Turnover in Early Acute Respiratory Distress Syndrome

Cited by 64 publications

References 19 publications

Repair after Acute Lung Injury: Molecular Mechanisms and Therapeutic Opportunities

Repair after Acute Lung Injury: Molecular Mechanisms and Therapeutic Opportunities

Regulatory T Cells Reduce Acute Lung Injury Fibroproliferation by Decreasing Fibrocyte Recruitment

Always cleave up your mess: targeting collagen degradation to treat tissue fibrosis

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