Acute respiratory distress syndrome (ARDS) presents a complex pathophysiology characterized by pulmonary activated coagulation and reduced fibrinolysis. Despite advances in supportive care of this syndrome, morbidity and mortality remains high, leading to the need of novel therapies to combat this disease. Focus these therapies in the inhibition of ARDS development pathophysiology is essential. Beneficial effects of anticoagulants in ARDS have been proved in preclinical and clinical trials, thanks to its anticoagulant and anti-inflammatory properties. Moreover, local administration by nebulization in the alveolar compartment increases local efficacy and does not produce systemic bleeding. In this review the coagulation and fibrinolytic pathway and its pharmacological targets to treat ARDS are summarized.
Sepsis and acute respiratory distress syndrome (ARDS) are life threating diseases with high mortality and morbidity in all the critical care units around the world. After decades of research, and numerous pre-clinical and clinical trials, sepsis and ARDS remain without a specific and effective pharmacotherapy and essentially the management remains supportive. In the last years cell therapies gained potential as a therapeutic treatment for ARDS and sepsis. Based on numerous pre-clinical studies, there is a growing evidence of the potential benefits of cell based therapies for the treatment of sepsis and ARDS. Several cell types are used in the last years for the treatment of both syndromes showing high efficiency. Embryonic stem cells (ESC), multipotent stem (or stromal) cells (MSC) and epithelial progenitors cells (EpPC) have been used for both diseases. Nowadays, the major part of the pre-clinical studies are using MSC, however other relevant groups are also using induced pluripotent stem cells (iPSC) for the treatment of both syndromes and alveolar type II cells for ARDS treatment. Numerous questions need further study including: determining the best source for the progenitor cells isolation, their large scale production and cryopreservation. Also, the heterogeneity of patients with sepsis and ARDS is massive, and establish a target population or the stratification of the patients will help us to determine better the therapeutic effect of these cell therapies. In this review we are going to describe briefly the different cell types, their potential sources and characteristics and mechanism of action. Here, also we elucidate the results of several pre-clicinical and clinical studies in ARDS and in sepsis and the future directions of these studies.
The defining features of acute respiratory distress syndrome (ARDS) are an excessive inflammatory respiratory response associated with high morbidity and mortality. Treatment consists mainly of measures to avoid worsening lung injury and cannot reverse the underlying pathophysiological process. New pharmacological agents have shown promising results in preclinical studies; however, they have not been successfully translated to patients with ARDS. The lack of effective therapeutic interventions has resulted in a recent interest in strategies to prevent ARDS with treatments delivering medications directly to the lungs by inhalation and nebulization, hopefully minimizing systemic adverse events. We analyzed the effect of different aerosolized drugs such as bronchodilators, corticosteroids, pulmonary vasodilators, anticoagulants, mucolytics and surfactant. New therapeutic strategies and ongoing trials using carbon monoxide (CO) and AP301 peptide are also briefly reviewed.
Background
During acute respiratory distress syndrome, proinflammatory mediators inhibit natural anticoagulant factors, which alter the normal balance between coagulation and fibrinolysis leading to a procoagulant state. We hypothesize that pulmonary administration of anticoagulants might be beneficial to treat acute respiratory distress syndrome for their anticoagulant and antiinflammatory effects and reduce the risk of systemic bleeding.
Objectives
Our aim is to study the effects of nebulized antithrombin (AT) and combined AT and heparin in an animal model of acute lung injury.
Methods
Acute lung injury was induced in rats by the intratracheal administration of hydrochloric acid and lipopolysaccharide. AT alone (500 IU/kg body weight) or combined with heparin (1000 IU/kg body weight) were nebulized after the injury. Control groups received saline instead. Blood, lung tissue, bronchoalveolar lavage, and alveolar macrophages (AM) isolated from bronchoalveolar lavage were collected after 48 hours and analyzed.
Results
Nebulized anticoagulant treatments reduced protein concentration in the lungs and decreased injury‐mediated coagulation factors (tissue factor, plasminogen activator inhibitor‐1, plasminogen, and fibrinogen degradation product) and inflammation (tumor necrosis factor α and interleukin 1β) in the alveolar space without affecting systemic coagulation and no bleeding. AT alone reduced fibrin deposition and edema in the lungs. Heparin did not potentiate AT coagulant effect but promoted the reduction of macrophages infiltration into the alveolar compartment. Anticoagulants reduced nuclear factor‐kB downstream effectors in AM.
Conclusions
Nebulized AT and heparin attenuate lung injury through decreasing coagulation and inflammation without altering systemic coagulation and no bleeding. However, combined AT and heparin did not produce a synergistic effect.
The use of cell therapies has recently increased for the treatment of pulmonary diseases. Mesenchymal stem/stromal cells (MSCs) and alveolar type II cells (ATII) are the main cell-based therapies used for the treatment of acute respiratory distress syndrome (ARDS). Many pre-clinical studies have shown that both therapies generate positive outcomes; however, the differences in the efficiency of MSCs or ATII for reducing lung damage remains to be studied. We compared the potential of both cell therapies, administering them using the same route and dose and equal time points in a sustained acute lung injury (ALI) model. We found that the MSCs and ATII cells have similar therapeutic effects when we tested them in a hydrochloric acid and lipopolysaccharide (HCl-LPS) two-hit ALI model. Both therapies were able to reduce proinflammatory cytokines, decrease neutrophil infiltration, reduce permeability, and moderate hemorrhage and interstitial edema. Although MSCs and ATII cells have been described as targeting different cellular and molecular mechanisms, our data indicates that both cell therapies are successful for the treatment of ALI, with similar beneficial results. Understanding direct cell crosstalk and the factors released from each cell will open the door to more accurate drugs being able to target specific pathways and offer new curative options for ARDS.
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