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In this article we review recent advances made in the pathophysiology, diagnosis, and treatment of inhalation injury. Historically, the diagnosis of inhalation injury has relied on nonspecific clinical exam findings and bronchoscopic evidence. The development of a grading system and the use of modalities such as chest computed tomography may allow for a more nuanced evaluation of inhalation injury and enhanced ability to prognosticate. Supportive respiratory care remains essential in managing inhalation injury. Adjuncts still lacking definitive evidence of efficacy include bronchodilators, mucolytic agents, inhaled anticoagulants, nonconventional ventilator modes, prone positioning, and extracorporeal membrane oxygenation. Recent research focusing on molecular mechanisms involved in inhalation injury has increased the number of potential therapies.

Smoke inhalation injury (SII) is the most common cause of death in burn patients who are victims of fire. The inflammatory response to smoke inhalation is an important factor leading to acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), so finding effective anti-inflammatory targets is the key to treating SII. Our previous study demonstrated that bone marrow mesenchymal stem cells (BMSCs) can regulate the M2-type polarization of alveolar macrophages, inhibit the inflammatory response, and have a good therapeutic effect on SII. However, the potential mechanism remains largely unknown. The immune checkpoint molecule CD200 is an important player in the immunomodulatory function of MSCs. However, whether CD200, as an immune molecule that targets macrophages, could be a new anti-inflammatory target for treating SII has not been reported. To delineate the role of the immune checkpoint CD200 in this process, we employed an in vitro co-culture system of BMSCs and alveolar macrophages, employing siRNA-mediated knockdown to specifically inhibit CD200 expression in BMSCs. The effects of CD200 knockdown on macrophage polarization and associated molecular pathways were subsequently investigated. For in vivo validation, a rat model of smoke inhalation injury was established to evaluate the therapeutic efficacy of CD200-deficient BMSCs on lung injury and macrophage polarization. Our study revealed that BMSCs significantly promoted the M2-type polarization of alveolar macrophages. In contrast, the ability of BMSCs to promote the conversion of M1 to M2 macrophages was significantly diminished by knocking down CD200. These observations suggest that the regulatory effect of BMSCs on alveolar macrophage polarization is partly mediated through the CD200-CD200R pathway. Mechanistically, this regulation was associated with CD200-CD200R-mediated suppression of c-Jun N-terminal kinase (JNK) activity in alveolar macrophages. In vivo, we further confirmed that CD200 knockdown significantly downregulated the regulatory effect of BMSCs on M1/M2 macrophage polarization in rats with SII, which in turn attenuated the therapeutic effect of BMSCs on lung injury after smoke inhalation. Our findings identify the immune checkpoint molecule CD200 as an anti-inflammatory target in the regulation of alveolar macrophages by BMSCs and provide new insights for more effective and precise MSC-based cell therapy.

Fire smoke inhalation represents a major cause of acute mortality in fire incidents, with hydrogen cyanide being a critical contributor to rapid systemic toxicity. This study aimed to establish a controlled smoke inhalation model to characterize cyanide-dominant exposure and to evaluate the prophylactic efficacy of a nebulized antidote combination under acute conditions. A reproducible smoke chamber system was developed to generate cyanide-rich toxic atmospheres. C57BL/6 mice were exposed to controlled cyanide concentrations, followed by prophylactic administration of a nebulized formulation containing hydroxocobalamin and deferoxamine. Survival outcomes were assessed to evaluate the protective effects of the intervention. Controlled cyanide exposure resulted in rapid and dose-dependent lethality. Prophylactic inhalation of the nebulized antidote significantly improved short-term survival compared with untreated controls (p < 0.05), consistent with effective mitigation of cyanide toxicity. In conclusion, this study establishes a reproducible cyanide-focused smoke inhalation model and provides experimental evidence supporting the potential of aerosolized hydroxocobalamin-based prophylaxis as an immediate protective strategy during fire smoke exposure. These findings support the feasibility of rapid, non-invasive intervention aimed at preserving a critical time window for escape and subsequent medical treatment in fire-related emergencies.

Background Myocardial infarction is the leading cause of death in fire fighters and has been linked with exposure to air pollution and fire suppression duties. We therefore investigated the effects of wood smoke exposure on vascular vasomotor and fibrinolytic function, and thrombus formation in healthy fire fighters. Methods In a double-blind randomized cross-over study, 16 healthy male fire fighters were exposed to wood smoke (~1 mg/m 3 particulate matter concentration) or filtered air for one hour during intermittent exercise. Arterial pressure and stiffness were measured before and immediately after exposure, and forearm blood flow was measured during intra-brachial infusion of endothelium-dependent and -independent vasodilators 4–6 hours after exposure. Thrombus formation was assessed using the ex vivo Badimon chamber at 2 hours, and platelet activation was measured using flow cytometry for up to 24 hours after the exposure. Results Compared to filtered air, exposure to wood smoke increased blood carboxyhaemoglobin concentrations (1.3% versus 0.8%; P < 0.001), but had no effect on arterial pressure, augmentation index or pulse wave velocity (P > 0.05 for all). Whilst there was a dose-dependent increase in forearm blood flow with each vasodilator (P < 0.01 for all), there were no differences in blood flow responses to acetylcholine, sodium nitroprusside or verapamil between exposures (P > 0.05 for all). Following exposure to wood smoke, vasodilatation to bradykinin increased (P = 0.003), but there was no effect on bradykinin-induced tissue-plasminogen activator release, thrombus area or markers of platelet activation (P > 0.05 for all). Conclusions Wood smoke exposure does not impair vascular vasomotor or fibrinolytic function, or increase thrombus formation in fire fighters. Acute cardiovascular events following fire suppression may be precipitated by exposure to other air pollutants or through other mechanisms, such as strenuous physical exertion and dehydration. Trial registration ClinicalTrials.gov Identifier: NCT01495325 .

Burns are tissue traumas caused by energy transfer and occur with a variable inflammatory response. The consequences of burns represent a public health problem worldwide. Inhalation injury (II) is a severity factor when associated with burn, leading to a worse prognosis. Its treatment is complex and often involves invasive mechanical ventilation (IMV). The primary purpose of this study will be to assess the evidence regarding the frequency and mortality of II in burn patients. The secondary purposes will be to assess the evidence regarding the association between IIs and respiratory complications (pneumonia, airway obstruction, acute respiratory failure, acute respiratory distress syndrome), need for IMV and complications in other organ systems, and highlight factors associated with IIs in burn patients and prognostic factors associated with acute respiratory failure, need for IMV and mortality of II in burn patients. This is a systematic literature review and meta-analysis, according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA). PubMed/MEDLINE, Embase, LILACS/VHL, Scopus, Web of Science, and CINAHL databases will be consulted without language restrictions and publication date. Studies presenting incomplete data and patients under 19 years of age will be excluded. Data will be synthesized through continuous (mean and standard deviation) and dichotomous (relative risk) variables and the total number of participants. The means, sample sizes, standard deviations from the mean, and relative risks will be entered into the Review Manager web analysis software (The Cochrane Collaboration). Despite the extensive experience managing IIs in burn patients, they still represent an important cause of morbidity and mortality. Diagnosis and accurate measurement of its damage are complex, and therapies are essentially based on supportive measures. Considering the challenge, their impact, and their potential severity, IIs represent a promising area for research, needing further studies to understand and contribute to its better evolution. The protocol of this review is registered on the International prospective register of systematic reviews platform of the Center for Revisions and Disclosure of the University of York, United Kingdom (https://www.crd.york.ac.uk/prospero), under number RD42022343944.

Background Acute respiratory distress syndrome (ARDS) is multifactorial and can result from sepsis, trauma, or pneumonia, amongst other primary pathologies. It is one of the major causes of death in critically ill patients with a reported mortality rate up to 45%. The present study focuses on the development of a large animal model of smoke inhalation-induced ARDS in an effort to provide the scientific community with a reliable, reproducible large animal model of isolated toxic inhalation injury-induced ARDS. Methods Animals (n = 21) were exposed to smoke under general anesthesia for 1 to 2 h (median smoke exposure = 0.5 to 1 L of oak wood smoke) after the ultrasound-guided placement of carotid, pulmonary, and femoral artery catheters. Peripheral oxygen saturation (SpO 2 ), vital signs, and ventilator parameters were monitored throughout the procedure. Chest x-ray, carotid, femoral and pulmonary artery blood samples were collected before, during, and after smoke exposure. Animals were euthanized and lung tissue collected for analysis 48 h after smoke inhalation. Results Animals developed ARDS 48 h after smoke inhalation as reflected by a decrease in SpO 2 by approximately 31%, PaO 2 /FiO 2 ratio by approximately 208 (50%), and development of bilateral, diffuse infiltrates on chest x-ray. Study animals also demonstrated a significant increase in IL-6 level, lung tissue injury score and wet/dry ratio, as well as changes in other arterial blood gas (ABG) parameters. Conclusions This study reports, for the first time, a novel large animal model of isolated smoke inhalation-induced ARDS without confounding variables such as cutaneous burn injury. Use of this unique model may be of benefit in studying the pathophysiology of inhalation injury or for development of novel therapeutics.

Lung injury resulting from inhalation of smoke or chemical products of combustion continues to be associated with significant morbidity and mortality. Combined with cutaneous burns, inhalation injury increases fluid resuscitation requirements, incidence of pulmonary complications and overall mortality of thermal injury. While many products and techniques have been developed to manage cutaneous thermal trauma, relatively few diagnosis-specific therapeutic options have been identified for patients with inhalation injury. Several factors explain slower progress for improvement in management of patients with inhalation injury. Inhalation injury is a more complex clinical problem. Burned cutaneous tissue may be excised and replaced with skin grafts. Injured pulmonary tissue must be protected from secondary injury due to resuscitation, mechanical ventilation and infection while host repair mechanisms receive appropriate support. Many of the consequences of smoke inhalation result from an inflammatory response involving mediators whose number and role remain incompletely understood despite improved tools for processing of clinical material. Improvements in mortality from inhalation injury are mostly due to widespread improvements in critical care rather than focused interventions for smoke inhalation. Morbidity associated with inhalation injury is produced by heat exposure and inhaled toxins. Management of toxin exposure in smoke inhalation remains controversial, particularly as related to carbon monoxide and cyanide. Hyperbaric oxygen treatment has been evaluated in multiple trials to manage neurologic sequelae of carbon monoxide exposure. Unfortunately, data to date do not support application of hyperbaric oxygen in this population outside the context of clinical trials. Cyanide is another toxin produced by combustion of natural or synthetic materials. A number of antidote strategies have been evaluated to address tissue hypoxia associated with cyanide exposure. Data from European centers supports application of specific antidotes for cyanide toxicity. Consistent international support for this therapy is lacking. Even diagnostic criteria are not consistently applied though bronchoscopy is one diagnostic and therapeutic tool. Medical strategies under investigation for specific treatment of smoke inhalation include beta-agonists, pulmonary blood flow modifiers, anticoagulants and antiinflammatory strategies. Until the value of these and other approaches is confirmed, however, the clinical approach to inhalation injury is supportive.

The overexpression of inducible nitric oxide synthase (iNOS) induces cell apoptosis through various signal transduction pathways and aggravates lung injury. Caspase-3 is an important protein in the apoptotic pathway and its activation can exacerbate apoptosis. Simvastatin, a hydroxymethyl glutaryl-A reductase inhibitor, protects against smoke inhalation injury by inhibiting the synthesis and release of inflammatory factors and decreasing cell apoptosis. Following the establishment of an animal model of smoke inhalation injury, lung tissue and serum were collected at different time points and the protein and mRNA expression of iNOS and caspase-3 in lung tissue by immunochemistry, western blot and reverse transcription-quantitative polymerase chain reaction, the malondialdehyde (MDA) content and superoxide dismutase (SOD) activity in lung tissue and serum were analyzed using thiobarbituric acid method and the WST-1 method. The results were statistically analyzed. The lung tissues of the rats in the saline group and the low-, middle- and high-dose groups exhibited clear edema and hemorrhage, and had significantly higher pathological scores at the various time points compared with the rats in the control group (P<0.05). Furthermore, lung tissue and serum samples obtained from these four groups had significantly higher mRNA and protein expression levels of iNOS and caspase-3 (P<0.05), significantly lower SOD activity and higher MDA content (P<0.05). Compared with the saline group, the low-, middle- and high-dose groups had significantly lower pathological scores (P<0.05), significantly lower mRNA and protein expression levels of iNOS, caspase-3 and MDA content in lung tissues (P<0.05) and significantly higher SOD activity in lung tissues and serum. The middle- and high-dose groups had significantly lower pathological scores (P<0.05), significantly decreased iNOS and caspase-3 mRNA and protein expression in lung tissues, significantly higher SOD activity in lung tissues and serum and a significantly lower MDA content (P<0.05) compared with the low-dose group. With the exception of SOD activity in lung tissues at 24 and 72 h and MDA content in serum at 48 h, no significant differences were observed between the middle- and high-dose groups. The present study demonstrated that there was an association between the therapeutic effect and dosage of simvastatin within a definitive range. In rats with smoke inhalation injury, simvastatin inhibited iNOS and caspase-3 expression in lung tissues and mitigated oxidative stress, thereby exerting a protective effect. In addition, the effect and dose were associated within a definitive range.

Background Smoke inhalation injury increases overall burn mortality by up to 20 times. Current therapy remains supportive with a failure to identify an optimal or targeted treatment protocol for smoke inhalation injury. The goal of this review is to describe emerging therapies that are being developed to treat the pulmonary pathology induced by smoke inhalation injury with or without concurrent burn injury. Main body A comprehensive literature search was performed using PubMed (1995–present) for therapies not approved by the U.S. Food and Drug Administration (FDA) for smoke inhalation injury with or without concurrent burn injury. Therapies were divided based on therapeutic strategy. Models included inhalation alone with or without concurrent burn injury. Specific animal model, mechanism of action of medication, route of administration, therapeutic benefit, safety, mortality benefit, and efficacy were reviewed. Multiple potential therapies for smoke inhalation injury with or without burn injury are currently under investigation. These include stem cell therapy, anticoagulation therapy, selectin inhibition, inflammatory pathway modulation, superoxide and peroxynitrite decomposition, selective nitric oxide synthase inhibition, hydrogen sulfide, HMG-CoA reductase inhibition, proton pump inhibition, and targeted nanotherapies. While each of these approaches shows a potential therapeutic benefit to treating inhalation injury in animal models, further research including mortality benefit is needed to ensure safety and efficacy in humans. Conclusions Multiple novel therapies currently under active investigation to treat smoke inhalation injury show promising results. Much research remains to be conducted before these emerging therapies can be translated to the clinical arena.

Smoke inhalation injury is a serious medical problem that increases morbidity and mortality after severe burns. However, relatively little attention has been paid to this devastating condition, and the bulk of research is limited to preclinical basic science studies. Moreover, no worldwide consensus criteria exist for its diagnosis, severity grading, and prognosis. Therapeutic approaches are highly variable depending on the country and burn centre or hospital. In this Series paper, we discuss understanding of the pathophysiology of smoke inhalation injury, the best evidence-based treatments, and challenges and future directions in diagnostics and management.