BackgroundAcute lung injury (ALI) is characterized by suppressed fibrinolytic activity in bronchoalveolar lavage fluid (BALF) attributed to elevated plasminogen activator inhibitor-1 (PAI-1). Restoring pulmonary fibrinolysis by delivering tissue-type plasminogen activator (tPA), urokinase plasminogen activator (uPA), and plasmin could be a promising approach.ObjectivesTo systematically analyze the overall benefit of fibrinolytic therapy for ALI reported in preclinical studies.MethodsWe searched PubMed, Embase, Web of Science, and CNKI Chinese databases, and analyzed data retrieved from 22 studies for the beneficial effects of fibrinolytics on animal models of ALI.ResultsBoth large and small animals were used with five routes for delivering tPA, uPA, and plasmin. Fibrinolytics significantly increased the fibrinolytic activity both in the plasma and BALF. Fibrin degradation products in BALF had a net increase of 408.41 ng/ml vs controls (P < 0.00001). In addition, plasma thrombin–antithrombin complexes increased 1.59 ng/ml over controls (P = 0.0001). In sharp contrast, PAI-1 level in BALF decreased 21.44 ng/ml compared with controls (P < 0.00001). Arterial oxygen tension was improved by a net increase of 15.16 mmHg, while carbon dioxide pressure was significantly reduced (11.66 mmHg, P = 0.0001 vs controls). Additionally, fibrinolytics improved lung function and alleviated inflammation response: the lung wet/dry ratio was decreased 1.49 (P < 0.0001 vs controls), lung injury score was reduced 1.83 (P < 0.00001 vs controls), and BALF neutrophils were lesser (3 × 104/ml, P < 0.00001 vs controls). The mortality decreased significantly within defined study periods (6 h to 30 days for mortality), as the risk ratio of death was 0.2-fold of controls (P = 0.0008).ConclusionWe conclude that fibrinolytic therapy may be effective pharmaceutic strategy for ALI in animal models.
The ENaC/degenerin ion channel superfamily includes the amiloride-sensitive epithelial sodium channel (ENaC) and acid sensitive ionic channel (ASIC). ENaC is a multimeric ion channel formed by heteromultimeric membrane glycoproteins, which participate in a multitude of biological processes by mediating the transport of sodium (Na+) across epithelial tissues such as the kidney, lungs, bladder, and gut. Aberrant ENaC functions contribute to several human disease states including pseudohypoaldosteronism, Liddle syndrome, cystic fibrosis, and salt-sensitive hypertension. Increasing evidence suggests that ion channels not only regulate ion homeostasis and electric signaling in excitable cells but also play important roles in cancer cell behaviors such as proliferation, apoptosis, invasion, and migration. Indeed, ENaCs/ASICs had been reported to be associated with cancer characteristics. Given their cell surface localization and pharmacology, pharmacological strategies to target ENaC/ASIC family members may be promising cancer therapeutics.
Smoke-inhalation-induced acute lung injury (SI-ALI) is a leading cause of morbidity and mortality in victims of fire tragedies. SI-ALI contributes to an estimated 30% of burn-caused patient deaths, and recently, more attention has been paid to the specific interventions for this devastating respiratory illness. In the last decade, much progress has been made in the understanding of SI-ALI patho-mechanisms and in the development of new therapeutic strategies in both preclinical and clinical studies. This article reviews the recent progress in the treatment of SI-ALI, based on pathophysiology, thermal damage, airway obstruction, the nuclear-factor kappa-B signaling pathway, and oxidative stress. Preclinical therapeutic strategies include use of mesenchymal stem cells, hydrogen sulfide, peroxynitrite decomposition catalysts, and proton-pump inhibitors. Clinical interventions include high-frequency percussive ventilation, perfluorohexane, inhaled anticoagulants, and nebulized epinephrine. The animal model, dose, clinical application, and pharmacology of these medications are summarized. Future directions and further needs for developing innovative therapies are discussed.
Respiratory diseases, which are leading causes of mortality and morbidity in the world, are dysfunctions of the nasopharynx, the trachea, the bronchus, the lung and the pleural cavity. Symptoms of chronic respiratory diseases, such as cough, sneezing and difficulty breathing, may seriously affect the productivity, sleep quality and physical and mental well-being of patients, and patients with acute respiratory diseases may have difficulty breathing, anoxia and even life-threatening respiratory failure. Respiratory diseases are generally heterogeneous, with multifaceted causes including smoking, ageing, air pollution, infection and gene mutations. Clinically, a single pulmonary disease can exhibit more than one phenotype or coexist with multiple organ disorders. To correct abnormal function or repair injured respiratory tissues, one of the most promising techniques is to correct mutated genes by gene editing, as some gene mutations have been clearly demonstrated to be associated with genetic or heterogeneous respiratory diseases. Zinc finger nucleases (ZFN), transcription activator-like effector nucleases (TALEN) and clustered regulatory interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) systems are three innovative gene editing technologies developed recently. In this short review, we have summarised the structure and operating principles of the ZFNs, TALENs and CRISPR/Cas9 systems and their preclinical and clinical applications in respiratory diseases.
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