Circulating fibrocytes traffic to the lung in murine acute lung injury and predict outcomes in human acute respiratory distress syndrome: a pilot study

Abstract

Background Fibrosis is an integral component of the pathogenesis of acute lung injury and is associated with poor outcomes in patients with acute respiratory distress syndrome (ARDS). Fibrocytes are bone marrow-derived cells that traffic to injured tissues and contribute to fibrosis; hence their concentration in the peripheral blood has the potential to serve as a biomarker of lung fibrogenesis. We therefore sought to test the hypothesis that the concentration and phenotype of circulating fibrocytes in patients with ARDS predicts clinical outcomes. Methods For the animal studies, C57Bl/6 mice were infected with experimental Klebsiella pneumoniae in a model of acute lung injury; one-way ANOVA was used to compare multiple groups and two-way ANOVA was used to compare two groups over time. For the human study, 42 subjects with ARDS and 12 subjects with pneumonia (without ARDS) were compared to healthy controls. Chi-squared or Fisher’s exact test were used to compare binary outcomes. Survival data was expressed using a Kaplan-Meier curve and compared by log-rank test. Univariable and multivariable logistic regression were used to predict death. Results In mice with acute lung injury caused by Klebsiella pneumonia, there was a time-dependent increase in lung soluble collagen that correlated with sequential expansion of fibrocytes in the bone marrow, blood, and then lung compartments. Correspondingly, when compared via cross-sectional analysis, the initial concentration of blood fibrocytes was elevated in human subjects with ARDS or pneumonia as compared to healthy controls. In addition, fibrocytes from subjects with ARDS displayed an activated phenotype and on serial measurements, exhibited intermittent episodes of markedly elevated concentration over a median of 1 week. A peak concentration of circulating fibrocytes above a threshold of > 4.8 × 106 cells/mL cells correlated with mortality that was independent of age, ratio of arterial oxygen concentration to the fraction of inspired oxygen, and vasopressor requirement. Conclusions Circulating fibrocytes increase in a murine model of acute lung injury and elevation in the number of these cells above a certain threshold is correlated with mortality in human ARDS. Therefore, these cells may provide a useful and easily measured biomarker to predict outcomes in these patients.

Circulating fibrocytes as prognostic biomarkers of autoimmune interstitial lung disease

“…Importantly, the predictive value of fibrocytes was cumulative and continuous, conferring a 5% increased risk per 10 5 increase in fibrocyte concentration, and was independent of the gender–age–physiology score and UIP pattern, each of which have previously been linked to worse outcomes in autoimmune ILD [ 28 , 29 , 37 , 38 ]. The threshold value of fibrocyte concentration identified in this study is similar to the values we identified in patients with Hermansky–Pudlak syndrome, chronic sickle cell lung disease and post-acute respiratory distress syndrome (ARDS) pulmonary fibrosis [ 13 , 27 , 39 ].…”

“…Blood samples were collected in heparinised tubes and immediately placed on ice, then refrigerated overnight before processing for fibrocytes quantification by flow cytometry without ex vivo manipulations such as culture or enrichment, as previously described [ 13 , 25 – 27 ]. See the online supplementary material (supplementary appendix S1) for detailed methods and gating strategy.…”

Pulmonary fibrosis in the aftermath of the Covid-19 era (Review)

“…Fibrocytes have been shown to expand in the blood in the context of both physiologic wound repair and several diseases associated with fibrogenesis. As it is shown that the presence of fibrocytes in the BAL in ARDS correlates with poor outcomes (28), a recent study evaluated the expansion of fibrocytes in the bone marrow, blood, and lung of animal models of lung injury (29). Furthermore, a similar pattern in blood fibrocytes in patients with lung injury was described, the extent of which was predictive of outcomes (29), supporting the idea that fibrocytes could represent a useful biomarker.…”

Blood fibrocytes are associated with severity and prognosis in COVID-19 pneumonia

“…Lin et al previously reported that circulating fibrocytes displayed intermittent episodes of marked elevation in ARDS patients evaluated serially over their ICU stay (22). However, this is the first report of a sustained increase of circulating fibrocytes several months after the initial lung injury.…”

“…Alveolar fibrocytes may originate from the recruitment of circulating fibrocytes to the lung mainly through the CXCR4-CXCL12 axis, and from local differentiation of monocytes in alveolar spaces, which is promoted by pro-fibrotic cytokines (IL-4, IL-13, TGF-β1) and inhibited by serum amyloid P (SAP) component, interferon-gamma and IL-12 (18)( 19) (20). In ARDS, increased blood fibrocyte counts are associated with increased mortality (21) (22).…”