Airway Tissue Plasminogen Activator Prevents Acute Mortality Due to Lethal Sulfur Mustard Inhalation

To review: a) the role of extravascular fibrin deposition in the pathogenesis of acute lung injury; b) the abnormalities in the coagulation and fibrinolysis pathways that promote fibrin deposition in the acutely injured lung; and c) the pathways that contribute to the regulation of the fibrinolytic system via the lung epithelium, including newly recognized posttranscriptional and urokinase-dependent pathways. Another objective was to determine how novel anticoagulant or fibrinolytic strategies may be used to protect against acute inflammation or accelerated fibrosis in acute lung injury. Published medical literature. Alveolar fibrin deposition is characteristic of diverse forms of acute lung injury. Intravascular thrombosis or disseminated intravascular coagulation can also occur in the acutely injured lung. Extravascular fibrin deposition promotes lung dysfunction and the acute inflammatory response. In addition, transitional fibrin in the alveolar compartment undergoes remodeling leading to accelerated pulmonary fibrosis similar to the events associated with wound healing, or desmoplasia associated with solid neoplasms. In acute lung injury, alveolar fibrin deposition is potentiated by consistent changes in endogenous coagulation and fibrinolytic pathways. Procoagulant activity is increased in conjunction with depression of fibrinolytic activity in the alveolar compartment. Initiation of the procoagulant response occurs as a result of local overexpression of tissue factor associated with factor VII. Depression of fibrinolytic activity occurs as a result of inhibition of urokinase plasminogen activator (uPA) by plasminogen activators, or series inhibition of plasmin by antiplasmins. Locally increased amplification of plasminogen activator inhibitor-1 (PAI-1) is largely responsible for this fibrinolytic defect. Newly described pathways by which lung epithelial cells regulate expression of uPA, its receptor uPAR, and PAI-1 at the posttranscriptional level have been identified. These pathways operate by cis-trans interactions between mRNA binding proteins; regulatory sequences within these mRNAs control their stability. The regulatory mechanisms seem to involve multiple protein-mRNA interactions, and the phosphorylation state of the proteins appears to determine whether complex formation of, or dissociation from, the regulatory sequences occurs. uPA is capable of inducing its own expression in lung epithelial cells as well as that of uPAR and PAI-1-the effects involve posttranscriptional regulatory components. These and related observations have led to the implementation of anticoagulant or fibrinolytic strategies to protect the lung against acute lung injury. The success of new fibrinolytic strategies to block pleural loculation suggests that a similar approach might be used to prevent accelerated pulmonary fibrosis, which can occur in association with many forms of acute lung injury. Disordered coagulation and fibrinolysis promote extravascular fibrin deposition in acute lung injury. It is this deposition that characterizes acute lung injury and repair. Expression of uPA, uPAR, and PAI-1 by the lung epithelium, as well as the ability of uPA to induce other components of the fibrinolytic system, involves posttranscriptional regulation. These pathways may contribute to disordered fibrin turnover in the injured lung. The success of anticoagulant or fibrinolytic strategies designed to reverse the abnormalities of local fibrin turnover in acute lung injury supports the inference that abnormalities of coagulation, fibrinolysis, and fibrin deposition have a critical role in the pathogenesis of acute lung injury.

Sulfur mustard is an alkylating agent that reacts with ocular, respiratory, cutaneous, and bone marrow tissues, resulting in early and late toxic effects. We compare these effects based on the experience in Iranian veterans exposed to the agent during the Iran-Iraq conflict (1983-88). The first clinical manifestations of sulfur mustard poisoning occurred in the eyes with a sensation of grittiness, lacrimation, photophobia, blepharospasm, and corneal ulceration. Respiratory effects appeared as rhinorhea, laryngitis, tracheobronchitis, and dyspnoea. Skin lesions varied from erythema to bullous necrotization. Initial leukocytosis and lymphopenia returned to normal within four weeks in recovered patients, but marked cytopenia with bone marrow failure occurred in fatal cases. Late toxic effects of sulfur mustard were most commonly found in lungs, skin and eyes. Main respiratory complications were chronic obstructive pulmonary disease, bronchiectasis, asthma, large airway narrowing, and pulmonary fibrosis. Late skin lesions were hyperpigmentation, dry skin, atrophy, and hypopigmentation. Fifteen of the severely intoxicated patients were diagnosed with delayed keratitis, having corneal vascularization, thinning, and epithelial defect. Respiratory complications exacerbated over time, while cutaneous and ocular lesions decreased or remained constant. Both the severity and frequency of bronchiectatic lesions increased during long-term follow-up. The only deteriorating cutaneous complication was dry skin. The maximum incidence of delayed kaeratitis was observed 15 to 20 years after initial exposure. Being suggested as the main cause ofassociated with malignancies and recurrent infections, natural killer cells were significantly lower 16 to 20 years after intoxication.

Sulfur mustard (SM) is a strong vesicant agent which has been used in several military conflicts. Large stockpiles still exist to the present day. SM is believed to be a major threat to civilian populations because of the persistent asymmetric threat by non-state actors, such as terrorist groups, its easy synthesis and handling and the risk of theft from stockpiles. Following an asymptomatic interval of several hours, acute SM exposure produces subepidermal skin blisters, respiratory tract damage, eye lesions and bone marrow depression. Iranian victims of SM exposure during the Iran-Iraq (1984-1988) war were treated at intensive care units of 3 Munich hospitals. All 12 patients were injured following aerial attacks with SM filled bombs, which exploded in a distance between 5 and 30m. All patients soon noted an offensive smell of garlic, addle eggs or oil roasted vegetables. No individual protective equipment was used. Eye itching and skin blistering started 2h after SM exposure. Some patients complained of nausea, dizziness and hoarseness. 4h after exposure, most patients started vomiting. Eye symptoms worsened and most patients suffered from temporary blindness due to blepharospasm and lid oedema. Additionally, pulmonary symptoms such as productive cough occurred. Patients were transferred to Munich 4-17 days after SM exposure. On admission all patients showed significant skin blistering and pigmentation. Conjunctivitis and photophobia were the major eye symptoms. Pulmonary symptoms, including productive cough were persistent. Bronchoscopy revealed massive inflammation of the trachea with signs of necrosis. 3 patients needed tracheotomy. Chest X-ray did not yield abnormal observations. This presentation summarizes the experience of treating SM victims in Munich and discusses therapeutic implications.