An Official American Thoracic Society Workshop Report: Chemical Inhalational Disasters. Biology of Lung Injury, Development of Novel Therapeutics, and Medical Preparedness

Juncos

American Journal of Physiology-Heart and Circulatory Physiology

et al. 2019

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Halogens are widely used, highly toxic chemicals that pose a potential threat to humans because of their abundance. Halogens such as bromine (Br2) cause severe pulmonary and systemic injuries; however, the mechanisms of their toxicity are largely unknown. Here, we demonstrated that Br2 and reactive brominated species produced in the lung and released in blood reach the heart and cause acute cardiac ultrastructural damage and dysfunction in rats. Br2-induced cardiac damage was demonstrated by acute (3–24 h) increases in circulating troponin I, heart-type fatty acid-binding protein, and NH2-terminal pro-brain natriuretic peptide. Transmission electron microscopy demonstrated acute (3–24 h) cardiac contraction band necrosis, disruption of z-disks, and mitochondrial swelling and disorganization. Echocardiography and hemodynamic analysis revealed left ventricular (LV) systolic and diastolic dysfunction at 7 days. Plasma and LV tissue had increased levels of brominated fatty acids. 2-Bromohexadecanal (Br-HDA) injected into the LV cavity of a normal rat caused acute LV enlargement with extensive disruption of the sarcomeric architecture and mitochondrial damage. There was extensive infiltration of neutrophils and increased myeloperoxidase levels in the hearts of Br2- or Br2 reactant-exposed rats. Increased bromination of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) and increased phosphalamban after Br2 inhalation decreased cardiac SERCA activity by 70%. SERCA inactivation was accompanied by increased Ca2+-sensitive LV calpain activity. The calpain-specific inhibitor MDL28170 administered within 1 h after exposure significantly decreased calpain activity and acute mortality. Bromine inhalation and formation of reactive brominated species caused acute cardiac injury and myocardial damage that can lead to heart failure. NEW & NOTEWORTHY The present study defines left ventricular systolic and diastolic dysfunction due to cardiac injury after bromine (Br2) inhalation. A calpain-dependent mechanism was identified as a potential mediator of cardiac ultrastructure damage. This study not only highlights the importance of monitoring acute cardiac symptoms in victims of Br2 exposure but also defines calpains as a potential target to treat Br2-induced toxicity.

Section: Introductionmentioning

confidence: 99%

Bromine inhalation mimics ischemia-reperfusion cardiomyocyte injury and calpain activation in rats

Juncos

American Journal of Physiology-Heart and Circulatory Physiology

et al. 2019

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“…Additional therapies of potential benefit include inhaled betaagonists and N-acetylcysteine, as well as ibuprofen. 37,38,[43][44][45] After phosgene exposure, bed rest and close observation are recommended, with oxygen supplementation delayed until it is clinically required to prevent hypoxemia. If oxygen therapy is necessary, it should target oxygen saturation at the low end of the normal range in order to mitigate oxidant-induced injury.…”

Section: Primary Respiratory Irritantsmentioning

confidence: 99%

“…43,44 Delayed or persistent effects of respiratory irritants include airway hyperreactivity, or reactive airways dysfunction syndrome, characterized by acute bronchoconstrictor responses to otherwise innocuous concentrations of inhaled agents, 46,47 as well as interstitial pulmonary fibrosis, emphysema, bronchiectasis, and bronchiolitis obliterans. 37,39,45…”

Section: Primary Respiratory Irritantsmentioning

confidence: 99%

Hazardous Chemical Emergencies and Poisonings

2019

H azardous chemical emergencies and related poisonings result from various exposures, including inadvertent residential, industrial, occupational, or transportation mishaps; natural disasters; and hazardoussubstance releases that are intended to cause harm. 1-3 Up to 100,000 industrial chemicals are used each day in the United States, 4 and federal authorities estimate that more than 10,000 potentially consequential releases of hazardous substances occur annually. 4,5 In addition, numerous compounds have been developed primarily as military weapons, with exceedingly high toxicity. 6-8 Both toxic industrial chemicals and military chemical weapons are capable of causing mass casualties in a substantive release and may be deployed intentionally in the context of chemical terrorism, 8-10 targeted assassination attempts, 8,11,12 or wartime attacks on civilian populations, as tragically shown in the current Syrian war. 13,14 A toxidrome-based, emergency medical systems (EMS) approach to chemical weapons attacks was presented recently by Ciottone in the Journal. 8 (Toxidromes are constellations of clinical signs, particularly vital signs, mental status, and ocular, respiratory, neurologic, and skin findings, that are characteristic of general classes of poison.) A similar approach is useful for the myriad possible entities in nonintentional hazardous chemical incidents. We review the toxicology and hospital-based management of acute poisonings caused principally by dermal and inhalational exposure to several representative chemical-agent classes in incidents involving the release of hazardous substances or chemical attacks (Table 1). Cyanide and organophosphate poisonings are emphasized, since they can also affect individual patients in the more familiar contexts of occupational and residential exposures or ingestions with suicidal intent and since specific emergency antidotal therapy is crucial for good outcomes. Ov erv iew of Hospita l-Ba sed Emergenc y M a nagement Incidents involving the release of hazardous chemicals may result in widespread chaos and confusion, affecting the EMS response and emergency department (ED) care. 2,8 A rapid influx of multiple critically ill victims with unfamiliar illnesses, as well as numerous low-risk but understandably anxious patients, potentially far outnumbering the seriously ill, 1 poses significant challenges to hospital-based emergency care providers. Patients may bypass prehospital care and arrive at the hospital unaware of or misinformed regarding the cause of their symptoms, with the potential to chemically contaminate bystanders and staff. 2,15-17 Thus, prompt recognition of the chemical event is important so that ED staff and hospital emergency management personnel can secure hospital entrances and decontaminate contami

Annals of the New York Academy of Sciences

“…Of the 71 persons hospitalized for acute health effects because of Cl 2 exposure, one died in the hospital and 25 (35%) were admitted to intensive care, with a median length of stay of 3 days 15 . The number of hospital admissions for pulmonary and nonpulmonary causes subsequently increased significantly following the release of Cl 2 in South Carolina 16 . Eight‐ to 10‐months after the Graniteville incident cough and shortness of breath were still persistent in victims 17 .…”

Section: Introduction and Purposementioning

confidence: 99%

“…Patients who survive ALI from any source often develop chronic lung disease with airflow obstruction, fibrosis, 18 AHR, and impaired gas exchange 14,19–21 . These patients often require hospitalization 6,16 and are predisposed to bacterial infections 22 . AHR, also termed reactive airways dysfunction syndrome, has also been reported in individuals exposed to Cl 2 , and asthma‐like symptoms can persist for long periods 15,23 …”

Section: Introduction and Purposementioning

confidence: 99%

Hyaluronan and halogen‐induced airway hyperresponsiveness and lung injury

Lazrak

Song

Zhou

et al. 2020

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Chlorine (Cl 2) and bromine (Br 2) are produced in large quantities throughout the world and used in the industry and the sanitation of water. These halogens can pose a significant threat to public health when released into the atmosphere during transportation and industrial accidents, or as acts of terrorism. In this review, we discuss the evidence showing that the activity of Cl 2 and Br 2 , and of products formed by their interaction with biomolecules, fragment high-molecular-weight hyaluronan (HMW-HA), a key component of the interstitial space and present in epithelial cells, to form proinflammatory, low-molecular-weight hyaluronan fragments that increase intracellular calcium (Ca 2+) and activate RAS homolog family member A (RhoA) in airway smooth muscle and epithelial and microvascular cells. These changes result in airway hyperresponsiveness (AHR) to methacholine and increase epithelial and microvascular permeability. The increase in intracellular Ca 2+ is the result of the activation of the calcium-sensing receptor by Cl 2 , Br 2 , and their by-products. Posthalogen administration of a commercially available form of HMW-HA to mice and to airway cells in vitro reverses the increase of Ca 2+ and the activation of RhoA, and restores AHR to near-normal levels of airway function. These data have established the potential of HMW-HA to be a countermeasure against Cl 2 and Br 2 toxicity.