Alveolar fibroblasts in acute lung injury: biological behaviour and clinical relevance

Quesnel, Christophe; Nardelli, L; Piednoir, Pascale; Leçon, Véronique; Marchal-Sommé, Joëlle; Lasocki, Sigismond; Bouadma, Lila; Philip, Ivan; Stolzmann, Paul; Crestani, Bruno; Dehoux, Monique

doi:10.1183/09031936.00074709

Cited by 46 publications

(43 citation statements)

References 42 publications

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“…They are present in the BAL fluid and blood of patients with IPF, and increased fibrocyte numbers predict exacerbations (14,16). Fibrocytes are also found in the BAL fluid of patients with ARDS, and are associated with increased mortality (17,18). CXCL12 is constitutively expressed in a number of tissues, and binds to the CXCR4 receptor on fibrocytes to promote migration (12,14,(35)(36)(37).…”

Section: Discussionmentioning

confidence: 99%

“…Fibrocytes are contained in the bronchoalveolar lavage (BAL) and blood of patients with idiopathic pulmonary fibrosis (IPF), and may predict exacerbations (14,16). Recently, fibrocytes were found in the BAL of patients with ARDS, and were associated with increased mortality (17,18). The mechanisms governing fibrocyte recruitment and activation in ALI remain unknown.…”

Section: Cd25mentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Cd25mentioning

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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“…Fibroblasts and myofibroblasts are the predominant cell types involved in pulmonary fibrogenesis and can originate from local precursors such as interstitial fibroblasts, from EMT of abnormally activated alveolar epithelium, or from circulating fibrocytes derived from bone marrow recruited to the lung. 18,30 Three primary factors driving the differentiation of fibroblasts to myofibroblasts are high mechanical Figure 5 Src-deficient mice and PP2 abrogated lung stretch-induced epithelial-mesenchymal transition and Src phosphorylation in fibroblasts. Five days after administering bleomycin, representative micrographs ( Â 400) with a-smooth muscle actin (a-SMA, red), collagen I (Col I, bright green) and Hoechst (blue) immunofluorescent staining of fibroblasts (a) were from the nonventilated control mice and those subjected to V T at 30 ml/kg for 5 h with room air (n ¼ 5 per group).…”

Section: Discussionmentioning

confidence: 99%

“…10 Previous studies of ARDS patients have also demonstrated that alveolar fibroblasts can be cultured in the organic phase of ARDS patients, and blocking the TGF-b1 receptor can attenuate lung fibrogenesis. 30,31 Increased production of TGF-b1 can bind to ECM, which is responsible for transmitting mechanical stretch between cells. 32 Disturbances in coagulation and fibrinolysis, related to elevated pulmonary concentrations of PAI-1, have been demonstrated in patients with ARDS.…”

Section: Discussionmentioning

confidence: 99%

Mechanical ventilation augments bleomycin-induced epithelial–mesenchymal transition through the Src pathway

Liu

Kao

et al. 2014

Laboratory Investigation

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Mechanical ventilation used in patients with acute respiratory distress syndrome (ARDS) can damage pulmonary epithelial cells by producing inflammatory cytokines and depositing excess collagen. Src participates in plasminogen activator inhibitor-1 (PAI-1) and transforming growth factor-b1(TGF-b1) production during the fibroproliferative phase of ARDS, which involves a process of epithelial-mesenchymal transition (EMT). The mechanisms regulating interactions between mechanical ventilation and EMT are unclear. We hypothesized that EMT induced by high-tidal volume (V T ) mechanical stretch-augmented lung inflammation occurs through upregulation of the Src pathway. Five days after administering bleomycin to simulate acute lung injury (ALI), male C57BL/6 mice, either wild-type or Src-deficient, aged 3 months, weighing between 25 and 30 g, were exposed to low-V T (6 ml/kg) or high-V T (30 ml/kg) mechanical ventilation with room air for 1-5 h. Nonventilated mice were used as control subjects. We observed that high-V T mechanical ventilation increased microvascular permeability, PAI-1 and TGF-b1 protein levels, Masson's trichrome staining, extracellular collagen levels, collagen gene expression, fibroblast accumulation, positive staining of a-smooth muscle actin and type I collagen, activation of Src signaling and epithelial apoptotic cell death in wild-type mice (Po0.05). Decreased staining of the epithelial marker, Zonula occludents-1, was also observed. Mechanical stretch-augmented EMT and epithelial apoptosis were attenuated in Src-deficient mice and pharmacological inhibition of Src activity by PP2 (Po0.05). Our data suggest that high-V T mechanical ventilation-augmented EMT after bleomycin-induced ALI partially depends on the Src pathway. Acute respiratory distress syndrome (ARDS) is a disorder of acute respiratory failure and manifests as non-cardiogenic pulmonary edema, respiratory distress and hypoxemia. 1,2 Mechanical ventilation with high-tidal volume (V T ) causes severe lung injury (ventilator-induced lung injury (VILI)) characterized by an initial inhomogeneous inflammatory reaction or epithelial injury that is followed by a fibroproliferative phase with fibroblast proliferation. 3-8 Epithelialmesenchymal transition (EMT) is the differentiation of epithelial cells into myofibroblast-like cells, which contributes to the fibroproliferative phase. 3-8 Upregulating Src, the plasminogen activator inhibitor-1 (PAI-1), and the transforming growth factor-b1(TGF-b1) has recently been demonstrated to regulate EMT. 9-14 However, the mechanisms regulating the interactions between mechanical ventilation and EMT remain unclear.PAI-1, a member of the serine protease inhibitor (serpin) gene family, rapidly inhibits both the urokinase-type plasminogen activator and the tissue-type plasminogen activator (tPA). 15 Mice with homozygous deletion of PAI-1 were relatively protected from bleomycin-induced pulmonary fibrogenesis, whereas overexpression of PAI-1 enhanced pulmonary fibrogenesis. 9 As a primary profibrogenic cytokine...

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“…For instance, Chesnutt et al [26] reported that a procollagen concentration above 1.75 U/ml had a positive predictive value for death of 0.75. However, a recent article by Quesnel et al [27] showed that patients with ALI/acute respiratory distress syndrome (ARDS) with fi broblasts in their alveolar fl uid had increased levels of type I procollagen, a decreased pro-infl ammatory response (lower neutrophil count, decreased IL-8 levels), and improved prognosis, suggesting a switch from infl ammation and tissue destruction to alveolar repair.…”

Section: Signs Of Tissue Repair In Patientsmentioning

confidence: 99%

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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Alveolar fibroblasts in acute lung injury: biological behaviour and clinical relevance

Cited by 46 publications

References 42 publications

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

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

Mechanical ventilation augments bleomycin-induced epithelial–mesenchymal transition through the Src pathway

Repair after Acute Lung Injury: Molecular Mechanisms and Therapeutic Opportunities

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