Progenitor potential of lung epithelial organoid cells in a transplantation model.

Lung progenitor cells are crucial for regeneration following injury, yet it is unclear whether lung progenitor cells can be functionally engrafted after transplantation. We transplanted organoid cells derived from alveolar type II (AT2) cells enriched by SCA1-negative status (SNO) or multipotent SCA1-positive progenitor cells (SPO) into injured mouse lungs. Transplanted SNO cells are retained in the alveolar regions, whereas SPO cells incorporate into airway and alveolar regions. Single-cell transcriptomics demonstrate that transplanted SNO cells are comparable to native AT2 cells. Transplanted SPO cells exhibit transcriptional hallmarks of alveolar and airway cells, as well as transitional cell states identified in disease. Transplanted cells proliferate after re-injury of recipient mice and retain organoid-forming capacity. Thus, lung epithelial organoid cells exhibit progenitor cell functions after reintroduction to the lung. This study reveals methods to interrogate lung progenitor cell potential and model transitional cell states relevant to pathogenic features of lung disease in vivo.

Air-liquid interface culture promotes maturation and allows environmental exposure of pluripotent stem cell-derived alveolar epithelium.

Type 2 alveolar epithelial cells (AT2s), facultative progenitor cells of the lung alveolus, play a vital role in the biology of the distal lung. In vitro model systems that incorporate human cells, recapitulate the biology of primary AT2s, and interface with the outside environment could serve as useful tools to elucidate functional characteristics of AT2s in homeostasis and disease. We and others recently adapted human induced pluripotent stem cell-derived AT2s (iAT2s) for air-liquid interface (ALI) culture. Here, we comprehensively characterize the effects of ALI culture on iAT2s and benchmark their transcriptional profile relative to both freshly sorted and cultured primary human fetal and adult AT2s. We find that iAT2s cultured at ALI maintain an AT2 phenotype while upregulating expression of transcripts associated with AT2 maturation. We then leverage this platform to assay the effects of exposure to clinically significant, inhaled toxicants including cigarette smoke and electronic cigarette vapor.

The aging lung: Physiology, disease, and immunity.

The population is aging at a rate never seen before in human history. As the number of elderly adults grows, it is imperative we expand our understanding of the underpinnings of aging biology. Human lungs are composed of a unique panoply of cell types that face ongoing chemical, mechanical, biological, immunological, and xenobiotic stress over a lifetime. Yet, we do not fully appreciate the mechanistic drivers of lung aging and why age increases the risk of parenchymal lung disease, fatal respiratory infection, and primary lung cancer. Here, we review the molecular and cellular aspects of lung aging, local stress response pathways, and how the aging process predisposes to the pathogenesis of pulmonary disease. We place these insights into context of the COVID-19 pandemic and discuss how innate and adaptive immunity within the lung is altered with age.

SARS-CoV-2 infection of primary human lung epithelium for COVID-19 modeling and drug discovery.

Coronavirus disease 2019 (COVID-19) is the latest respiratory pandemic caused by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). Although infection initiates in the proximal airways, severe and sometimes fatal symptoms of the disease are caused by infection of the alveolar type 2 (AT2) cells of the distal lung and associated inflammation. In this study, we develop primary human lung epithelial infection models to understand initial responses of proximal and distal lung epithelium to SARS-CoV-2 infection. Differentiated air-liquid interface (ALI) cultures of proximal airway epithelium and alveosphere cultures of distal lung AT2 cells are readily infected by SARS-CoV-2, leading to an epithelial cell-autonomous proinflammatory response with increased expression of interferon signaling genes. Studies to validate the efficacy of selected candidate COVID-19 drugs confirm that remdesivir strongly suppresses viral infection/replication. We provide a relevant platform for study of COVID-19 pathobiology and for rapid drug screening against SARS-CoV-2 and emergent respiratory pathogens.

Short-course, direct-acting antivirals and ezetimibe to prevent HCV infection in recipients of organs from HCV-infected donors: a phase 3, single-centre, open-label study.

BACKGROUND: An increasing percentage of potential organ donors are infected with hepatitis C virus (HCV). After transplantation from an infected donor, establishment of HCV infection in uninfected recipients is near-universal, with the requirement for post-transplant antiviral treatment. The aim of this study was to determine if antiviral drugs combined with an HCV entry blocker given before and for 7 days after transplant would be safe and reduce the likelihood of HCV infection in recipients of organs from HCV-infected donors. METHODS: HCV-uninfected organ recipients without pre-existing liver disease were treated with ezetimibe (10 mg; an HCV entry inhibitor) and glecaprevir-pibrentasvir (300 mg/120 mg) before and after transplantation from HCV-infected donors aged younger than 70 years without co-infection with HIV, hepatitis B virus, or human T-cell leukaemia virus 1 or 2. Recipients received a single dose 6-12 h before transplant and once a day for 7 days after surgery (eight doses in total). HCV RNA was assessed once a day for 14 days and then once a week until 12 weeks post-transplant. The primary endpoint was prevention of chronic HCV infection, as evidenced by undetectable serum HCV RNA at 12 weeks after transplant, and assessed in the intention-to-treat population. Safety monitoring was according to routine post-transplant practice. 12-week data are reported for the first 30 patients. The trial is registered on ClinicalTrials.gov, NCT04017338. The trial is closed to recruitment but follow-up is ongoing. FINDINGS: 30 patients (23 men and seven women; median age 61 years (IQR 48-66) received transplants (13 lung, ten kidney, six heart, and one kidney-pancreas) from 18 HCV-infected donors. The median donor viral load was 5·11 log10IU/mL (IQR 4·55-5·63) and at least three HCV genotypes were represented (nine [50%] donors with genotype 1, two [11%] with genotype 2, five [28%] with genotype 3, and two [11%] with unknown genotype). All 30 (100%) transplant recipients met the primary endpoint of undetectable HCV RNA at 12 weeks post-transplant, and were HCV RNA-negative at last follow-up (median 36 weeks post-transplant [IQR 25-47]). Low-level viraemia was transiently detectable in 21 (67%) of 30 recipients in the early post-transplant period but not after day 14. Treatment was well tolerated with no dose reductions or treatment discontinuations; 32 serious adverse events occurred in 20 (67%) recipients, with one grade 3 elevation in alanine aminotransferase (ALT) possibly related to treatment. Non-serious transient elevations in ALT and creatine kinase during the study dosing period resolved with treatment completion. Among the serious adverse events were two recipient deaths due to causes unrelated to study drug treatment (sepsis at 49 days and subarachnoid haemorrhage at 109 days post-transplant), with neither patient ever being viraemic for HCV. INTERPRETATION: Ezetimibe combined with glecaprevir-pibrentasvir given one dose before and for 7 days after transplant prevented the establishment of chronic HCV infection in recipients of different organs from HCV-infected donors. This study shows that an ultra-short course of direct-acting antivirals and ezetimibe can prevent the establishment of chronic HCV infection in the recipient, alleviating many of the concerns with transplanting organs from HCV-infected donors. FUNDING: Canadian Institutes of Health Research; the Organ Transplant Program, University Health Network.

Long-term use of left ventricular assist devices: a report on clinical outcomes.

BACKGROUND: The literature examining clinical outcomes and readmissions during extended (> 1 yr) left ventricular assist device (LVAD) support is scarce, particularly in the era of continuous-flow LVADs. METHODS: We completed a retrospective cohort study on consecutive LVAD patients from June 2006 to March 2015, focusing on those who received more than 1 year of total LVAD support time. Demographic characteristics, clinical outcomes and readmissions were analyzed using standard statistical methods. All readmissions were categorized as per the Interagency Registry for Mechanically Assisted Circulatory Support 2015 guidelines. RESULTS: Of the 103 patients who received LVADs during the study period, 37 received LVAD support for more than 1 year, with 18 receiving support for more than 2 years. Average support time was 786 ± 381 days, with total support time reaching 80 patient-years. During a median follow-up of 2 years, 27 patients died, with 1-year conditional survival of 74%. Median freedom from first readmission was 106 days (range 1-603 d), with an average length of stay of 6 days. Readmissions resulted in an average of 41 ± 76 days in hospital per patient. Reasons for readmission were major infection (24%), major bleeding (19%) and device malfunction/thrombus (13%). There were a total of 112 procedures completed during the readmissions, with 60% of procedures being done in 13% (n = 5) of patients. CONCLUSION: Continuous-flow LVADs provide excellent long-term survival. The present study describes marked differences in reasons for readmissions between the general LVAD population and those supported for more than 1 year. Prolonged LVAD support resulted in decreased susceptibility to major bleeds and increased susceptibility to infection.

CONTEXTE: La documentation sur les résultats cliniques et les réadmissions reliés au recours prolongé (> 1 an) à un dispositif d'assistance ventriculaire gauche (DAVG) est peu abondante, particulièrement en ce qui concerne les DAVG à flux continu. MÉTHODES: Nous avons procédé à une étude de cohorte rétrospective sur une série de patients consécutifs à qui on a implanté un DAVG entre juin 2006 et mars 2015, en nous attardant plus particulièrement à ceux qui ont bénéficié du DAVG pendant une durée totale de plus d'un an. Les caractéristiques démographiques, les résultats cliniques et les réadmissions ont été analysés au moyen de méthodes statistiques standard. Toutes les réadmissions ont été catégorisées selon les lignes directrices 2015 du Registre INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support). RÉSULTATS: Parmi les 103 patients chez qui un DAVG a été implanté durant la période de l'étude, 37 en ont bénéficié pendant plus d'un an et 18 pendant plus de 2 ans. La durée moyenne d'utilisation a été de 786 ± 381 jours, la durée totale de l'assistance ainsi fournie atteignant 80 années-patients. Pendant la période de suivi médiane de 2 ans, 27 patients sont décédés, ce qui correspond à une survie conditionnelle d'un an chez 74 % des participants. L'intervalle médian avant une première réadmission a été de 106 jours (éventail 1-603 jours), et la durée médiane des séjours a été de 6 jours. Les réadmissions ont en moyenne été suivies d'un séjour hospitalier de 41 ± 76 jours par patient. Les raisons des réadmissions ont été infection grave (24 %), hémorragie majeure (19 %) et dysfonction du dispositif/thrombus (13 %). En tout, 112 interventions ont été effectuées lors des réadmissions, 60 % d'entre elles chez 13 % des patients (n = 5). CONCLUSION: Les DAVG à flux continu donnent lieu à une excellente survie à long terme. La présente étude décrit les différences marquées en ce qui concerne les raisons des réadmissions entre la population générale porteuse d'un DAVG et la population ayant bénéficié du dispositif pendant plus d'un an. Le recours prolongé à un DAVG a été associé à une diminution du risque d'hémorragie majeure et à une augmentation du risque d'infection.

Erratum: Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2.

This corrects the article DOI: 10.1038/ncomms14922.

Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2.

Adenosquamous lung tumours, which are extremely poor prognosis, may result from cellular plasticity. Here, we demonstrate lineage switching of KRAS+ lung adenocarcinomas (ADC) to squamous cell carcinoma (SCC) through deletion of Lkb1 (Stk11) in autochthonous and transplant models. Chromatin analysis reveals loss of H3K27me3 and gain of H3K27ac and H3K4me3 at squamous lineage genes, including Sox2, ΔNp63 and Ngfr. SCC lesions have higher levels of the H3K27 methyltransferase EZH2 than the ADC lesions, but there is a clear lack of the essential Polycomb Repressive Complex 2 (PRC2) subunit EED in the SCC lesions. The pattern of high EZH2, but low H3K27me3 mark, is also prevalent in human lung SCC and SCC regions within ADSCC tumours. Using FACS-isolated populations, we demonstrate that bronchioalveolar stem cells and club cells are the likely cells-of-origin for SCC transitioned tumours. These findings shed light on the epigenetics and cellular origins of lineage-specific lung tumours.

Cigarette Smoke Enhances the Expression of Profibrotic Molecules in Alveolar Epithelial Cells.

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal disease of unknown etiology. A growing body of evidence indicates that it may result from an aberrant activation of alveolar epithelium, which induces the expansion of the fibroblast population, their differentiation to myofibroblasts and the excessive accumulation of extracellular matrix. The mechanisms that activate the alveolar epithelium are unknown, but several studies indicate that smoking is the main environmental risk factor for the development of IPF. In this study we explored the effect of cigarette smoke on the gene expression profile and signaling pathways in alveolar epithelial cells. Lung epithelial cell line from human (A549), was exposed to cigarette smoke extract (CSE) for 1, 3, and 5 weeks at 1, 5 and 10% and gene expression was evaluated by complete transcriptome microarrays. Signaling networks were analyzed with the Ingenuity Pathway Analysis software. At 5 weeks of exposure, alveolar epithelial cells acquired a fibroblast-like phenotype. At this time, gene expression profile revealed a significant increase of more than 1000 genes and deregulation of canonical signaling pathways such as TGF-ß and Wnt. Several profibrotic genes involved in EMT were over-expressed, and incomplete EMT was observed in these cells, and corroborated in mouse (MLE-12) and rat (RLE-6TN) epithelial cells. The secretion of activated TGF-ß1 increased in cells exposed to cigarette smoke, which decreased when the integrin alpha v gene was silenced. These findings suggest that the exposure of alveolar epithelial cells to CSE induces the expression and release of a variety of profibrotic genes, and the activation of TGF-ß1, which may explain at least partially, the increased risk of developing IPF in smokers.

Exposure of Monocytes to Lipoarabinomannan Promotes Their Differentiation into Functionally and Phenotypically Immature Macrophages.

Lipoarabinomannan (LAM) is a lipid virulence factor secreted by Mycobacterium tuberculosis (Mtb), the etiologic agent of tuberculosis. LAM can be measured in the urine or serum of tuberculosis patients (TB-patients). Circulating monocytes are the precursor cells of alveolar macrophages and might be exposed to LAM in patients with active TB. We speculated that exposing monocytes to LAM could produce phenotypically and functionally immature macrophages. To test our hypothesis, human monocytes were stimulated with LAM (24-120 hours) and various readouts were measured. The study showed that when monocytes were exposed to LAM, the frequency of CD68(+), CD33(+), and CD86(+) macrophages decreased, suggesting that monocyte differentiation into mature macrophages was affected. Regarding functionality markers, TLR2(+) and TLR4(+) macrophages also decreased, but the percentage of MMR(+) expression did not change. LAM-exposed monocytes generated macrophages that were less efficient in producing proinflammatory cytokines such as TNF-α and IFN-γ; however, their phagocytic capacity was not modified. Taken together, these data indicate that LAM exposure influenced monocyte differentiation and produced poorly functional macrophages with a different phenotype. These results may help us understand how mycobacteria can limit the quality of the innate and adaptive immune responses.

La formación ambiental en la educación superior: una revisión necesaria / Environmntal eduucation in higher education: a necesary review

El objetivo de este trabajo fue hacer una revisión y comparación de trabajos de investigación que han hecho contribuciones significativas al tema de la formación ambiental en la educación superior en Iberoamérica. Se revisan 51 trabajos de diferentes investigadores de nueve países (Argentina, Brasil, Chile, Colombia, Costa Rica, Cuba, España, México y Venezuela) que aportan argumentos conceptuales suficientes para derivar de allí los criterios con los cuales se ha realizado la formación ambiental en la educación superior en los últimos 15 años en los países de la región. Los criterios de análisis empleados para la revisión y comparación entre investigaciones fueron: ámbitos de la formación ambiental en las universidades, lo pedagógico, lo didáctico y el currículo en la formación ambiental universitaria. Como resultados principales se encuentra que, aunque se cuenta con experiencias enriquecedoras dirigidas a la innovación curricular, aún son muchos los procesos con tendencias hacia la visión fragmentada de la realidad, con currículos semejantes a planes de estudio y educación ambiental centrada en lo disciplinar. A modo de conclusión, se hace una propuesta de formación ambiental universitaria alternativa.

The aim of this research was to review and compare investigations of researches that have done significant contributions to the topic of environmental education in higher education in Latin America. A review of 51 works of different researchers of nine countries (Argentina, Brazil, Chile, Colombia, Costa Rica, Cuba, Spain, Mexico and Venezuela) that contribute with sufficient conceptual arguments to derive the criteria with which environmental education has been carried out in higher education institutions in the last 15 years in the countries of the region. The analysis criteria used for the review and comparison between researches were: areas of environmental education in the universities; and the pedagogical and the didactic and the curriculum in environmental education at the university. As principal results it is found that, though there are interesting and relevant experiences directed to curricular innovation, there are still many processes with trends towards the fragmented vision of reality, with curricula similar to plans of study and environmental education centered in disciplines. As a conclusion, the research proposes an alternative university environmental education.

Immunoglobulin free light chains are increased in hypersensitivity pneumonitis and idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF), a devastating lung disorder of unknown aetiology, and chronic hypersensitivity pneumonitis (HP), a disease provoked by an immunopathologic reaction to inhaled antigens, are two common interstitial lung diseases with uncertain pathogenic mechanisms. Previously, we have shown in other upper and lower airway diseases that immunoglobulin free light chains (FLCs) are increased and may be involved in initiating a local inflammation. In this study we explored if such a mechanism may also apply to HP and IPF. METHODS: In this study we examined the presence of FLC in serum and BAL fluid from 21 IPF and 22 HP patients and controls. IgG, IgE and tryptase concentrations were measured in BAL fluid only. The presence of FLCs, plasma cells, B cells and mast cells in lung tissue of 3 HP and 3 IPF patients and 1 control was analyzed using immunohistochemistry. RESULTS: FLC concentrations in serum and BAL fluid were increased in IPF and HP patients as compared to control subjects. IgG concentrations were only increased in HP patients, whereas IgE concentrations were comparable to controls in both patient groups. FLC-positive cells, B cells, plasma cells, and large numbers of activated mast cells were all detected in the lungs of HP and IPF patients, not in control lung. CONCLUSION: These results show that FLC concentrations are increased in serum and BAL fluid of IPF and HP patients and that FLCs are present within affected lung tissue. This suggests that FLCs may be involved in mediating pathology in both diseases.

Expression of matrix metalloproteases by fibrocytes: possible role in migration and homing.

RATIONALE: Fibrocytes are progenitor cells characterized by the simultaneous expression of mesenchymal, monocyte, and hematopoietic stem cell markers. We previously documented their presence in lungs of patients with idiopathic pulmonary fibrosis. However, the mechanisms involved in their migration, subsequent homing, and local role remain unclear. Matrix metalloproteinases (MMPs) facilitate cell migration and have been implicated in the pathogenesis of pulmonary fibrosis. OBJECTIVES: To evaluate the expression and role of matrix metalloproteinases in human fibrocytes. METHODS: Fibrocytes were purified from CD14(+) monocytes and cultured for 8 days; purity of fibrocyte cultures was 95% or greater as determined by flow cytometry. Conditioned media and total RNA were collected and the expression of MMP-1, MMP-2, MMP-7, MMP-8, and MMP-9 was evaluated by real-time polymerase chain reaction. Protein synthesis was examined using a Multiplex assay, Western blot, fluorescent immunocytochemistry, and confocal microscopy. MMP-2 and MMP-9 enzymatic activities were evaluated by gelatin zymography. Migration was assessed using collagen I-coated Boyden chambers. Stromal cell-derived factor-1α and platelet-derived growth factor-B were used as chemoattractant with or without a specific MMP-8 inhibitor. MEASUREMENTS AND MAIN RESULTS: Fibrocytes showed gene and protein expression of MMP-2, MMP-9, MMP-8, and MMP-7. MMP-2 and MMP-9 enzymatic activities were also demonstrated by gelatin zymography. Likewise, we found colocalization of MMP-8 and MMP-7 with type I collagen in fibrocytes. Fibrocyte migration toward platelet-derived growth factor-B or Stromal cell-derived factor-1α in collagen I-coated Boyden chambers was significantly reduced by a specific MMP-8 inhibitor. CONCLUSIONS: Our findings reveal that fibrocytes express a variety of MMPs and that MMP-8 actively participates in the process of fibrocyte migration.

FGF-1 reverts epithelial-mesenchymal transition induced by TGF-{beta}1 through MAPK/ERK kinase pathway.

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease characterized by the expansion of the fibroblast/myofibroblast population and aberrant remodeling. However, the origin of mesenchymal cells in this disorder is still under debate. Recent evidence indicates that epithelial-mesenchymal transition (EMT) induced primarily by TGF-beta1 plays an important role; however, studies regarding the opposite process, mesenchymal-epithelial transition, are scanty. We have previously shown that fibroblast growth factor-1 (FGF-1) inhibits several profibrogenic effects of TGF-beta1. In this study, we examined the effects of FGF-1 on TGF-beta1-induced EMT. A549 and RLE-6TN (human and rat) alveolar epithelial-like cell lines were stimulated with TGF-beta1 for 72 h, and then, in the presence of TGF-beta1, were cultured with FGF-1 plus heparin for an additional 48 h. After TGF-beta1 treatment, epithelial cells acquired a spindle-like mesenchymal phenotype with a substantial reduction of E-cadherin and cytokeratins and concurrent induction of alpha-smooth muscle actin measured by real-time PCR, Western blotting, and immunocytochemistry. FGF-1 plus heparin reversed these morphological changes and returned the epithelial and mesenchymal markers to control levels. Signaling pathways analyzed by selective pharmacological inhibitors showed that TGF-beta1 induces EMT through Smad pathway, while reversion by FGF-1 occurs through MAPK/ERK kinase pathway, resulting in ERK-1 phosphorylation and Smad2 dephosphorylation. These findings indicate that TGF-beta1-induced EMT is reversed by FGF-1 and suggest therapeutic approaches to target this process in IPF.

Guías de práctica clínica para el tratamiento del carcinoma escamocelular / Clinical guidelines for cutaneus squamous cell carcinoma treatment

El carcinoma escamocelular (CEC) ocupa el segundo puesto en frecuencia entre los cánceres de la de piel. Un grupo de CEC tiene un comportamiento biológico muy agresivo, y cursa con recurrencia local, metástasis y muerte. El evento etiológico principal es la radiación ultravioleta que induce el daño del DNA de los queratinocitos, especialmente en las personas blancas. Hay muchas variantes clínicas, cada una de ellas con un comportamiento biológico diferente. De igual modo, existen infinidad de variantes histológicas, pero la clasificación más adecuada es la que se basa en el patrón de crecimiento, porque éste refleja el comportamiento biológico y está en estrecha relación con el pronóstico. Tanto las características clínicas como las de histopatología son la base para que el dermatólogo decida el tratamiento óptimo en cada caso.

Fibrocytes are a potential source of lung fibroblasts in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis is characterized by the accumulation of fibroblasts/myofibroblasts and aberrant remodeling of the lung parenchyma. However, the sources of fibroblasts in IPF lungs are unclear. Fibrocytes are circulating progenitors of fibroblasts implicated in wound healing and fibrosis. In this study we evaluated evidence for the presence of fibrocytes in the lung of patients with idiopathic pulmonary fibrosis by immunofluorescence and confocal microscopy. Fibrocytes were identified in tissues in 8 out of 9 fibrotic lungs. Combinations including CXCR4 and a mesenchymal marker stained significantly more fibrocytes/mm(2) of tissue compared with combinations using CD34 or CD45RO with mesenchymal markers: CXCR4/procollagen-I (10.3+/-2.9fibrocytes/mm(2)) and CXCR4/prolyl-4-hydroxylase (4.1+/-3.1), versus CD34/procollagen-I (2.8+/-3.0), CD34/alphaSMA (2.2+/-1.6) and CD45RO/prolyl-4-hydroxylase (1.3+/-1.6); p<0.003. There was a positive correlation between the abundance of fibroblastic foci and the amount of lung fibrocytes (r=0.79; p<0.02). No fibrocytes were identified in normal lungs. The fibrocyte attractant chemokine CXCL12 increased in plasma [median: 2707.5pg/ml (648.1-4884.7) versus 1751.5pg/ml (192.9-2686.0) from healthy controls; p<0.003)] and was detectable in the bronchoalveolar lavage fluid of 40% of the patients but not in controls. In the lung CXCL12 was strongly expressed by alveolar epithelial cells. A negative correlation between plasma levels of CXCL12 with lung diffusing capacity for carbon monoxide (DLCO) (r=-0.56; p<0.03) and oxygen saturation on exercise was found (r=-0.41; p<0.04). These findings indicate that circulating fibrocytes, likely recruited through the CXCR4/CXCL12 axis, may contribute to the expansion of the fibroblast/myofibroblast population in idiopathic pulmonary fibrosis.

Evaluación del posible papel de la osteopontina como marcador biológico en la fibrosis pulmonar idiopática / Evaluation of osteopontin as a potential biological marker in idiopathic pulmonary fibrosis

Introducción: La fibrosis pulmonar idiopática (FPI) es una neumopatía crónica de difícil diagnóstico que puede confundirse con otras enfermedades pulmonares intersticiales difusas (EPID), por lo que es importante buscar nuevos métodos auxiliares para su diagnóstico. La osteopontina (OPN) es una glicoproteína multifuncional con efecto estimulante sobre los fibroblastos y la síntesis de matriz extracelular. Dado su posible papel profibrosante, consideramos de interés evaluar su concentración en el lavado bronquioalveolar (LBA) de pacientes con FPI y compararla con otras EPID. Material y métodos: La OPN se cuantificó por ELISA en 25 pacientes con FPI, 10 con neumonía intersticial no específica (NINE), 16 con neumonitis por hipersensibilidad (NH) y 10 controles sanos. Resultados: La concentración de OPN en pacientes con FPI fue significativamente mayor que en pacientes con NH y sanos (p < 0.0001) así como en pacientes con NINE (p < 0.05). Esta prueba mostró una sensibilidad de 80% y especificidad de 75% para el diagnóstico de FPI cuando el logaritmo de la concentración de OPN es de > 2.0. No hubo correlación entre los niveles de OPN con las pruebas de función pulmonar. Es interesante observar una asociación significativa entre los niveles de OPN y la presencia de hipocratismo digital (RM: 6.69; IC 1.25-10.76; p < 0.05). Conclusiones: La OPN se encuentra elevada en el LBA de pacientes con FPI por lo que podría considerarse como una prueba auxiliar en el diagnóstico diferencial de las EPID. Adicionalmente, nuestros hallazgos sugieren que la OPN puede estar implicada en la patogénesis del hipocratismo digital.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic pulmonary disease of difficult diagnosis that could be confused with other interstitial lung diseases (ILD). In this context, it is important to seek new methods which can be helpful in the diagnosis of this disease. Osteopontin (OPN) is a multifunctional glycopro-tein that has a stimulating effect over fibroblasts and extracellular matrix accumulation. Because it has a possible pro-fibrosing role, we decided to measure its concentration in bronchioalveolar lavage (BAL) from patients with IPF and to compare it with other ILDs. Methods: OPN concentration was measured by ELISA method in 25 IPF patients, 10 patients with non-specific interstitial pneumonia (NSIP), 16 patients with hypersensitivity pneumonitis (HP) and 10 healthy controls. Results: OPN levels in IPF patients were significantly increased compared with patients with HP and healthy controls (p < 0.0001) as with NSIP patients (p< 0.05). This test showed an 80% sensitivity and 75% specificity when the OPN concentration logarithm is > 2.0. There was no correlation between OPN levels and pulmonary function tests. Interestingly, we observed a significant association between OPN levels and finger clubbing (OR: 6.69; Cl: 1.25-10.76; p < 0.05). Conclusions: IPF patients showed increased OPN levels; this test might be considered as an ancillary tool in the differential diagnosis of ILD. Additionally, our findings suggest that OPN could be implicated in the pathogenesis of clubbing.