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Burns are the fourth most common cause of injury-related unintentional death worldwide. Pulmonary complications following acute smoke inhalation (ASI) are significant factors in the high morbidity and mortality seen in the burns patient. Over 30% of patients who suffer from ASI perish. Furthermore, inhalation injury predisposes the burns patient to pneumonia, increasing mortality risk by 90%.
The World Health Organisation states over 100 million people annually develop pulmonary inflammation from cooking stoves, forest fires, burning crops and industrial activities. Disaster events also precipitate ASI. Of the 790 surviving victims of the attacks on the World Trade Centre in 2001, 49% suffered from the acute effects of smoke.
Progress has been achieved in treating cutaneous burns by surgical excision and fluid resuscitation, although mortality in the ASI victim has remained steady for 20 years. The primary cause of death is carbon monoxide poisoning.
ASI injury is caused by the inhalation of noxious components of smoke. The severity of lung injury is dependent on the nature of the fire, and the materials under combustion. Smoke is heterogeneous and many constituents of smoke are asphyxiants, irritants and toxic. Entrapment in a closed environment increases the risk of sustaining a lung injury, whilst deep and rapid ventilation accrues greater amounts of smoke molecules in the tracheobronchial and parenchymal lung areas. The pathophysiology of ASI injury is described in light of current literature, followed by a discussion of the existing and potential pharmacological interventions in the ASI patient.
The physical and chemical nature of acute inhalation injury
The physical and chemical nature of smoke provides insight into the current poor prognosis in ASI victims. Smoke consists of a particulate and gas phase whilst the materials under combustion mediate the noxious gases present. Smoke toxins enter the airways and lungs, causing cell damage. Inhaled particles of soot >10µm are attenuated from reaching the lung parenchyma by respiratory type epithelium. Mucosa of the buccal cavity, pharynx, nasopharynx and eyes are irritated by polar molecules such as ammonia and hydrogen chloride. Hydrophobic compounds reach the lung parenchyma as isolated molecules. In contrast, hydrophilic molecules reach the parenchyma via soot particles of <5µm, which provide a surface for toxic hydrophilic compounds to be adsorbed.
Although the majority of burns victims die of acute carbon monoxide poisoning, a significant proportion initially survive yet suffer fatally from pulmonary complications, systemic inflammation and respiratory failure. These deaths are significant, because intervening in the pathogenesis of pulmonary dysfunction is a promising strategy to combat the effects of ASI.
Carbon monoxide poisoning is responsible for 50% of fire associated mortalities. A colourless, odourless, tasteless gas, carbon monoxide is created from the incomplete combustion of compounds containing carbon atoms. Carboxyheamoglobin (COHb) is formed when carbon monoxide combines with haemoglobin. Carbon monoxide competes with oxygen for occupation of the heam sites in haemoglobin, with a relative affinity of up to 270 times greater than oxygen. The dissociation curve of oxyheamoglobin is displaced to the left, impairing oxygen unloading to the tissues. Muscle anoxia occurs by the binding of carbon monoxide to myoglobin. Cellular adenosine triphospahte (ATP) generation falls, resulting in cell necrosis. The clinical diagnosis of carbon monoxide poisoning is complex , and co-oximetry is required to verify CO poisoning.
Hydrogen cyanide (HCN)
A colourless gas, HCN reversibly inhibits cytochrome c which is the final oxidase of the electron transport chain in mitochondria. HCN is produced by the combustion of materials such as synthetic polymers, silk, cotton and polyamides. Fatal blood concentrations vary from 1-5mg/l. Notably, HCN is a physiological metabolite, and is converted into thiocyanate. In high concentrations, HCN saturates the enzyme rhodanase. HCN poisoning is an important clinical diagnosis in ASI due to metabolic toxicity and the range of materials releasing it under combustion.
Complex hydrocarbons in smoke
Smoke contains particles of soot, and a diverse constellation of hydrocarbon molecules. Although heterogenous in structure, many hydrocarbons are irritant and carcinogenic.High concentrations of aldehydes occur in smoke, such as acrolein, and are NO 'generator molecules'. Halogens and nitrogen containing compounds from polymers contribute to parenchymal irritation,. Smoke also contains many reactive oxygen species. Polyvinyl chloride, polyethylene and polyurethane release toxic gases including chlorine, hydrocarbons, isocyante, ketones, aldehydes and hydrogen cyanide. Table 1 details common smoke toxins responsible for the morbid effects in ASI, and their respective sources.
Table 1 - Molecular contents of smoke, sources and effects
Name of chemical
Severe irritation, ONOO-production
Hypoxemia, COHb formed
The anatomy and physiology of smoke inhalation injury
Supra glottic (upper) airways
Thermal energy carried in smoke is disseminated in the nasopharynx, and thermal burns affect the supraglottic cavity superior to the vocal folds. Reflex contraction of the lateral cricoaretynoid muscles upon inspiration limits the volume of thermally destructive gas able to traverse the rima glottidis.
Particles of 5µm or less reach beyond the lung bronchioles, particles greater than this are filtered by respiratory type, ciliated pseudostratified columnar epithelium. The distribution of toxins in lung parenchymal tissue is proportional to tidal volume and respiratory rate. Particles of less than 1µm reach the alveoli, the acinar structures of gaseous exchange.
The inflammatory response to smoke
Sensory and vasomotor nerves abundantly innervate the respiratory tract, originating from the parasympathetic vagus nerve. Vagal fibres terminate in the epithelial layer of the airways, and respond acutely to inhaled smoke. Somatic c-fibres in the lung respond to pulmonary irritation, and are attributed to the release of histamine. The neurogenic pathway refers to the stimulation of these nerves in the pulmonary tissue.
Prolonged stimulation of the neurogenic pathway results in the release of local neuropeptides, aggravating local tissues, evidenced by the release of the pro-inflammatory markers bradykinin, substance P, calcitonin gene related peptide (CGRP, a potent vasodilator) and angiotensin II.
A cytokine storm is created in the respiratory tract, acting in concert with inhaled toxins to worsen outcome, by encouraging the extravasation of plasma proteins, smooth muscle contraction and increased mucus production in the tracheobronchial system.
The tracheobronchial area
Neurogenic stimulation in the conducting airway zone releases potent neuropeptides such as neurokinin-1 and substance P, which induce bronchoconstriction, initiating the complement cascade. Histamine is released and xanathine oxidase enzyme is transcribed. Xanathine oxidase synthesises uric acid, an intracellular 'danger signal'. Uric acid triggers NALP3 inflammasome production which increases interleukin-1 (IL1). The surge in cytokines upregulates iNOS enzyme, creating downstream reactive nitrogen species (RNS) such as peroxynitrite and reactive oxygen species (ROS).
ROS and RNS increase vascular permeability to plasma proteins and IL1 and IL8 are chemo-attractant to neutrophils (polymorphonuclear leukocytes). Neutrophil migration and activation approximates ROS and RNS to the airways and lung parenchyma. Airway mast cells and macrophages and intensify lung dysfunction by amplifying the production of cytokines.
Formation of local oedema results from the increase in endothelial permeability, mass trans-vascular flux of plasma proteins, and vasodilatation14-17. When managing burns patients, oedema formation is complicated by intravenous fluid resuscitation. Although required to treat shock and plasma loss, aggressive fluid management and mechanical ventilation may induce clinical trauma.
Neutral endopeptidase (NEP), a local regulatory enzyme, is released by lung epithelia and macrophages upon toxic insult. NEP activity hydrolyses peptide bonds of intercellular cytokines, thus limiting their actions. Unfortunately, the activity and presence of NEP is transient, due to the sloughing of airway epithelia following toxic insult. High protein transudation, exfoliation of epithelial cells and excessive mucus secretions obstruct the airways. Where formed, luminal occlusions are referred to as 'casts', and obstruct the tracheobronchial system. Tracheobronchial casts impede mechanical ventilation and contribute distal organ hypoxia. High pressure ventilation induces barotrauma to unoccluded alveoli, a clinical iatrogenicity of managing ASI in acute care. Tracheobronchial hallmarks of ASI are increased pulmonary shunt fraction, trans-pulmonary fluid flux, lung water retention and a reduction in the Pa O2:FiO2 (arterial O2:inspired fractional O2 ratio).
Systemic complications in the ASI injury
Bronchial blood enters the tracheobronchial circulation through bronchio-pulmonary vascular anastamoses. Burns over 30% of TBSA (the total body surface area) induce vascular hyperpermeability in the lung parenchyma, intestines and colon, which are characteristic of the systemic inflammatory response.
In an ovine model, ASI increased bronchial blood flow by a factor of 8. To limit the hyperaemic response, attenuation of bronchial perfusion, by surgical ligation of the bronchial arteries reduced fluid transudation and the clinical complications of oedema. The hyperaemic response is implicated as a forbearer of clinical complications in ASI.
Increased intestinal membrane permeability predisposes the ASI patient to sepsis, a macrocosmic consequence of ASI. Hyperaemic blood flow is attributed to iNOS formation, NO production and vasodilatation. Recent preclinical data suggests angiopoietin-1 has a major role in vascular protection in ASI models.
The lung parenchyma
Transvascular fluid flux, pulmonary shunting, direct alveolar collapse and atelectasis characterize ASI at the level of the lung parenchyma. Increased concentrations of NO in the blood induce endothelial smooth muscle relaxation and the subsequent loss of small vessel hypoxic vasoregulation. The destruction of alveolar surfactant attenuates inspiratory capacity and causes atelectasis resulting in sub-optimal gaseous exchange. The chemotactic cytokine storm attracts and activates polymorphonuclear leukocytes, which bind to the alveolar capillary membrane through L-selectin attachment, releasing RNS and ROS in close proximity to the alveolar membrane. Catastrophic pulmonary cell death exudes cellular casts by epithelial exfoliation into the tracheobronchial system, contributing to the formation of sputum and expectorant.
Molecular toxicology of lung injury
Metabolic reactions in cells create reactive oxygen species (ROS), (Table 1), (Figure 3). ROS are generated during combustion and are inhaled in large quantities in ASI. Superoxide, a highly reactive ROS, is generated by 1-5% of the oxygen undergoing single electron transfer in physiological mitochondrial respiration. ROS are able to initiate damage to vital cellular apparatus such through oxidative reaction with lipids and proteins. Under normophysiological concentrations, ROS production is controlled by cellular enzymes and antioxidant constituents of the cytosol such as superoxide dismutase (SOD), catalase enzyme (CAT) and glutathione peroxidase (GSH-Px).
Superoxide is physiologically converted by GSH, to H2O2 (hydrogen peroxide). Hydrogen peroxide is further reduced by CAT to H2O and O2. Hydrogen peroxide may undergo fission to create highly reactive hydroxyl radicals (OH*).
ROS are ubiquitous in smoke (Table 1), (Figure 3), and place oxidative stress on the lung airways. The physiological mechanisms controlling ROS are overburdened in the smoke inhalation injury, contributing to ROS induced cellular death.
Nuclear Factor Kappa Beta NF-κB release
NF-kB belongs to the 'Rel' group of transcription factor proteins. The cytokine surge is associated with the concomitant cytosolic release of nuclear factor kappa beta (NF-κB). Quiescent pulmonary cells contain NF-κB, which is sequestered by the dimeric protein complex inhibitory kappa-beta (IκB). Following molecular smoke injury, a signal transduction cascade phosphorylates and ubiquitinates serine residues of IκB via cAMP. NF-κB is released from complexed NF-κB-IκB and binds to the nuclear transcription factor p65, acting upon cytokine gene promoter sequences to promote the transcription of pro-inflammatory markers and stress-response-proteins. A pleiotrophic factor, NF-κB has a positive feedback effect on macrophage inflammatory protein-1, IL-1, IL-6, IL-8, and crucially the enzyme iNOS. c-Jun N-terminal Kinase activity is blocked by Nf-κB, crucially saving respiratory cells from apoptotic cell death. NF-kb is intimately linked to the apoptotic family of caspase enzymes.
Macrophages and endothelial cells exposed to the components of wood smoke were shown to upregulate NF-κB, in a dose dependent manner. Importantly, airway epithelia exposed to carbon soot, hypoxia and ROS upregulate NF-κB. The pharmacological blockade of NF-κB and related nuclear transcription products is of further interest in ASI to modulate cellular injury.
The production of nitric oxide (NO)
A soluble gas, NO is a vital physiological cellular signal and is central to the endothelial regulation of vascular tone. A neurotransmitter in inhibitory noradrenergic non cholinergic nerve cells (i-NANC), NO mediates i-NANC induced bronchodilation. The mechanisms of NO smooth muscle cell hyperpolarisation are yet to be fully determined, but one aspect of NO induced smooth muscle cell hyperpolarisation-relaxation is the interaction of NO with potassium (Kv) channels. Through Kv activation, cGMP is regenerated and intracellular [Ca2+] is sequestered by the sarcoplasmic reticulum,. NO is inextricably associated with inflammatory and physiological regulation and signalling.
Nitric oxide synthase enzyme (NOS) produces NO via oxidation of the guanidine group of L-arginine. In the reaction NADPH and O2 are utilised as cosubstrates. Three isoforms of NOS exist; two isoforms of NOS are considered constitutive (eNOS and nNOS). cNOS maintains a basal level of NO production. Endothelial and neuronal NOS isoforms are supplemented by inducible NOS (iNOS). iNOS is upregulated locally and systemically under the pathophysiological circumstances of ASI.
Cytokines (TNFα, interleukins, leukotrienes), and bacterial components (LPS, endotoxins) provoke iNOS synthesis in an array of cell lines, including endothelial cells and respiratory type epithelium. Type II respiratory pneumocytes release iNOS mRNA under the influence of oxidants. The mass induction of NOS in the lung parenchyma, tracheobronchial system and intestine has grave consequences for the burns patient.
First, NO induces systemic vasodilatation and inhibits hypoxic vasoconstriction in the lung, altering pulmonary ventilation:perfusion matching. Second, pulmonary dilatation and hyperaemia allows the migration of inflammatory cells deep into the parenchyma. Inflammatory consequences include cast formation, and in the intestines, altered permeability to enteral bacteria. Third, peroxynitrite formation (secondary to surplus ROS and NO) further contributes to vascular permeability, oedema and difficulty ventilating the patient. Therefore, the clinical sequelae of unmediated NO production are hospitalisation, intensive care admission, intubation and ventilation.
In ASI, ROS, such as superoxide and NO are abundant in the respiratory system. Peroxynitrite is conceived in a diffusion limited reaction between NO and superoxide. Peroxynitrite is highly cytotoxic and able to covalently modify cellular molecules, membrane lipids, cell proteins and DNA. Peroxynitrite inhibits mitochondrial respiratory enzymes and interferes with cell membrane signal transduction pathways,. Trans-peroxynitrous acid has been cited as the specific species responsible for DNA damage, causing modification of G-C base pairs (Figure 1). Toxicity of peroxynitrite is likely due to direct oxidative damage to zinc finger, heam group and thiol moieties. The production of iNOS is intimately linked to peroxynitrite formation, and should be considered a target for pharmacological intervention to mediate the consequences of peroxynitrite production.
The cis conformation of peroxynitrite is most stable in the cytosol. Protonation causes a conformational change to the reactive trans state, from the release of a reactive OH* hydroxyl radical and nitrogen dioxide molecule.
PARP (Poly-ADP-ribose enzyme)
DNA damage orchestrated by peroxynitrite activates the nuclear enzyme poly-ADP-ribose (PARP). A chromatin bound enzyme, PARP ribosylates nuclear DNA via the use of ADP. Under elevated pathophysiological concentrations of peroxynitrite, cellular energy is rapidly diminished via the process of PARP activation and ribosylation. DNA strand fracture in smoke inhalation is high, owing to the large amounts of ROS generated. PARP activation causes necrotic cell death by rapid use and depletion of intracellular ATP reserves. Necrosis of respiratory cells following smoke inhalation injury may be attributed to NO production, ROS generation-inhalation, downstream peroxynitrite formation and PARP activation. Ultimately, epithelial cells death contributes to bronchopulmonary congestion, difficulty in ventilation and increases risk of pneumonia in the intensive care setting.
Figure 2 - Pathophysiology of acute smoke inhalation injury
Inhalation of noxious molecules
Airway epithelium irritated
Bradykinin, Substance P, Angiotensin II, CGRP released
Chemotaxis: macrophages and neutrophils
Cellular release of
cytokines, eg/ IL1, TNF-a
Superoxide produced O2-
NF-κB uncoupled from IκB
Excess nitric oxide
Cellular ATP depletion
DNA strand fracture
Loss of hypoxic vasoconstriction
Pharmacological interventions in the ASI injury
The clinical foundations of ASI management are effective fluid resuscitation, airway ventilation and inflammatory modulation. Management of ASI is problematic, complicated by local oedema, cast formation and the increased risk of pneumonia upon intubation. If ASI is severe, fluid replacement may overload pulmonary tissues with extravasated plasma. In this section, current and innovative strategies in managing the inflammatory response to ASI are discussed.
Established drug regimens for pulmonary sequelae
ASI is treatable with drugs of various mechanisms, including β2-agonists, corticosteroids and anticoagulant agents. In paediatric cases, the mucolytic agent nebulised heparin (antithrombin) and antioxidant N-acetylcystine improve reintubation rates and ameliorate cast deposition. Heparin prevents fibrin formation in the tracheobronchial tree,. In adult cases of lung injury, randomised controlled are recommended to investigate the efficacy of mucolytic treatment.
Agonistic stimulation of β2 has therapeutic indications in ASI, dependant on cell type target. The β2 receptor is member to the super-family of seven transmembrane domain receptors, consisting of 413 amino acid residues. The β2 receptor is expressed in airway smooth muscle, mast cells and type II pneumocytes. In airway smooth muscle, β2 stimulation induces muscle relaxation, and increase forced expiratory volume [FEV].
Systemic and nebulised β2-agonists reduce airway resistance and lower the peak airway pressure. By improving lung compliance, barotrauma to the alveoli secondary to mechanical ventilation is reduced. β2-agonists yield an anti-inflammatory, antihistaminrgic profile and reduce TNF-α transcription, improving mucociliary clearance and endothelial permeability changes. β2 agonists reduce iNOS synthesis and inhibit promotional iNOS transcription factors such as NF-kB, a desireable mechanism in ASI. Extravascular lung oedema clearance is improved in acute respiratory distress syndrome (ARDS) by intravenous β2 agonist application, and pulmonary sequelae resolve favourably compared to non treatment groups. Tachycardia and hypokalemia complicate β2 agonist therapy and require adequate monitoring. Overall, β2 agonist therapy such as Albuterol and Salbutamol are promising future staples of ASI care, being easily obtainable and economic drug choices.
Intravenous corticosteroids dampen the pro-inflammatory response. Meta-analysis of randomised controlled trials and cohort studies indicates corticosteroids are a drug of choice in treating acute respiratory failure seen in burns patients, without unwanted systemic iatrogenicity.
Future treatment in ASI
Future pharmacological interventions will target inflammatory changes that precipitate pulmonary cast formation, extravasation of neutrophils and NO induction.
Recent by work Hassan and colleague's demonstrated ASI mortality is primarily due to acute respiratory distress opposed to other complications. The translocation of bacteria from the intestine in ASI is also a significant factor in critical care, promoting systemic septic complications.
The molecular mechanisms driving systemic inflammatory response syndrome (SIRS) following ASI are critical in orchestrating the release of cytokines and prognosis of the patient, therefore one should elect to explore treatments that ameliorate the increase in intestinal permeability following burn and ASI.
Intercepting the inflammatory cascade
Interleukins, cytokines, smoke toxins and bacterial lipopolysaccharide activate NF-κB, a nuclear transcription of iNOS. If NF-κB mediated inflammatory cytokines are pharmacologically managed, secondary effects of upregulated iNOS, NO and peroxynitrite may be preventable in ASI. (Figure 2, red boxes). Interception of NF-kb is likely to be double edged because NF-κB is crucial to anti-cell apoptosis. When examining NF-kB interception, mediators of the JNK induced apoptotic pathway should be monitored to prevent treatment induced cell death.
Recent work by Shalub and colleagues indicates polymorphisms for TNF-a and IL10 predict mortality in burns patients,. Pre-treatment of anti-IL8 in sheep improves pulmonary function by reducing lung tissue permeability. These data indicate management of cytokines may alleviate pulmonary dysfunction in ASI.
The inflammatory mediator CGRP is a potent vasodilator is released in burn and smoke injury. Inhibition of CGRP has demonstrated reduced hyperaemic and dilatory response to ASI in sheep. Currently, it is unknown if these data are linked to a reduction in iNOS transcription. Here, it is proposed IL8 and CRGRP attenuation may reduce iNOS production, and thus limit the NO induced hyperaemic response.
Currently, there is a paucity of literature regarding cytokine interference in ASI. It is clear various cytokines partake a cardinal role in the devastating hyperaemic changes to the pulmonary system following ASI. In the future, specific cytokine management may play a large role in controlling local and systemic inflammation in the burns patient.
The specific inhibition of iNOS opposed to cNOS (constitutive NOS isoforms) is desirable to prevent adverse physiological effects of generalised NOS inhibition, owing to the regulatory nature of cNOS. Whereas previously used compounds such as aminoguanidine S-methylthiourea are weakly specific to iNOS, new specific allosteric inhibitors of iNOS have been created. The molecules BBS-2 and L-N6-(1-lminoetyl)Lysine-5-tetrazole-amide are true allosteric inhibitors of iNOS,. The affinity of BBS-2 to iNOS is 1500 times than that of cNOS,,. However, iatrogenicity of these molecules is not documented, and these inhibitors are not yet approved for clinical use.
Histological inspection of ovine pulmonary tissue treated with BBS-2 versus control demonstrated lowered markers of vascular permeability, inflammation and oedema following induced burn and smoke injury. The role of iNOS in ASI pathology opposed to cNOS is therefore considerable. Moreover, the administration of non-specific NOS inhibitors is not without hazard: higher morbidity and mortality have been observed in patients receiving a non-specific inhibitor. Normophysiological levels of eNOS are critical to both cardiac and systemic endothelial regulation.
It has been theorized NOS isoform expression follows a temporal course of variation in ASI, although this review suggests the gross upregulation of iNOS is responsible for mass-NO formation. The effects of cNOS on ASI injury are proposed to be lesser, owing to the lack of evidence supporting neuronal or endothelial NOS upregulation in direct ASI injury. Currently, little experimental data supports a major role of cNOS in ASI. Recent work indicates nNOS inhibition improves pulmonary outcomes in ASI. However, nNOS is not directly upregulated in the lung following ASI, further implicating iNOS as the primary NO generator.
When exposed to E.coli lipopolysaccharide, bladder cells increase eNOS production. The function of eNOS in the inflammatory response is therefore not yet fully understood, and should be investigated further using models of smoke inhalation. By eliciting the temporal course of NOS isoform expression, it may be possible to target the inflammatory response in a protective manner germane to normophysiologic, essential NO generation.
If excessive NO production is successfully countered, mechanical airway management and nebulised drug delivery in the severely injured lung may be improved. The role of iNOS and eNOS inhibition in endothelial pulmonary regulation is of clinical interest, in order to improve pulmonary function in the intensive care scenario. To summarise, physiologically compatible NOS inhibitors should be investigated, and the temporal course of NOS isoforms expression in ASI fully determined to direct future pharmacological therapies.
Scavenging free radicals
N-acetyl cysteine (NAC) and α-tocopherol (a lipid peroxidation inhibitor, vitamin E) scavenge free radicals in cells, and have the capacity to repair damaged cellular constituents. Antioxidant combinations counter the effects of ROS and peroxynitrite induced cell death. In burns patients, α-tocopherol levels are documented to be vastly reduced. In burns patients, antioxidant trials have yielded lowered markers of oxidative stress and improvement in pulmonary function, and higher PaO2:FiO2 ratios were recorded with nebulised α-tocopherol administration.
A structural isomer of α-tocopherol, gamma-tocopherol potently binds NO. In a randomised controlled trial, the antioxidant ascorbic acid, (vitamin C) demonstrated improved PaO2:FiO2 ratios in a subgroup of ASI patients receiving supplementary ascorbic acid.
Scavenging damaging molecules by antioxidant administration is a promising future adjunctive therapy for ASI patients. Interdicting the pathways that produce excess ROS, NO and peroxynitrite in the acute smoke injury is a viable method of limiting cellular damage, epithelial sloughing, pulmonary dysfunction and the potentially mortal effects of a toxic insult to the airways.
The pharmacological inhibition of PARP may have therapeutic application in ASI injury, because PARP induced ATP depletion, pulmonary cell necrosis and subsequent sloughing is a major problem in ASI. Specific inhibitors such as 3-amino-benzamide protect cells from oxidant damage and cell death,, and reduce cytokine expression in acute lung inflammation models in sheep. These data suggest local positive feedback mechanisms in PARP activation and cytokine induction are present. In these models, increased cellular ATP concentrations and reduced necrotic cell death were documented. PARP inhibition has also demonstrated significant improvement in markers of vascular permeability and oedema. Therefore PARP inhibitors are of value in limiting the hyperaemic response in ASI. PARP inhibition may be favourable compared to NOS inhibition; bypassing the disadvantages of attenuating NO production. The loss of vascular hypo-contractility and energetic destruction of cells would be prevented. Pathogenic organisms do not encode PARP; therefore the polymorphonuclear generated ROS burst would not be disrupted, thus protecting the lung from invading microorganisms by maintaining peroxynitrite generation proximal to microbes. PARP inhibitors may serve as prophylaxis against hospital acquired pneumonia, by preserving endogenous antibiotic cellular defences, preventing cast formation and reducing expectorant and sputum in the ventilated patient, the pulmonary milieu would less conducive to pathogenic organisms. .
Pharmacological therapies that maintain airway integrity, reduce epithelial cell death and cast formation are likely to yield promising clinical applications in smoke inhalation injury.
Figure 2 (Flow chart: The Pathophysiology of ASI)
Figure 2 (Page 12) details the pathophysiology of ASI. Arrows indicate a stepwise temporal process between cell types. Orange represents initial steps, and red boxes are biochemical steps that may be targeted with drug therapies. Purple boxes are unwanted consequences of ASI that might be interdicted by drug administration.
Smoke is a mixture of toxic compounds that irritate the entire respiratory system. The chain of damaging cellular events following ASI has grave consequences for respiratory dynamics, consequently ASI Mortality is high in the acute care setting.
The central dogma of ARDS is the upregulation of iNOS and cytokines, which contribute significantly to death in ASI patients by altering membrane permeability and respiratory function,,,.
Current treatments for ASI are mostly supportive, such as mechanical ventilation.
iNOS inhibitors have been investigated, displaying favourable pulmonary outcomes in ovine models. There are numerous clinical benefits associated with iNOS inhibition, yet little is reported on effects of eNOS inhibition. The clinical effects of iNOS inhibition on ASI pulmonary hypotension are hypothesised to improve hypoxic regulation of the alveoli, dampening the deleterious hyperaemic response.
NF-κB is implicated early in airway response to ASI, upstream from cytokines and iNOS. Interference with NF-κB may alleviate sequelae of NO production, by lessening transcription products. Exploring the role of iNOS inhibitors and NF-κB antagonists in ASI NO pathophysiology is therefore an important area. As the molecular mechanisms that contribute to pulmonary failure are elucidated, pharmacological strategies suitable to ASI will become achievable.
In the future, treatment may intercept specific cytokines in a temporal process of inflammation-control management.
Attenuating pulmonary tissue damage from ASI promises to be a forthcoming gold standard of care. For the 30% of burns patients suffering the dire consequences of ASI, successful treatments cannot be translated to the bedside sooner.
Introduction to lab project
An investigation into the mechanisms of novel ASI drugs relative to their cellular effects will be undertaken, using a model of smoke inhalation injury. Isolated rat pulmonary artery in vitro will be stimulated with an NO generator. Using vessel myography, the response of the artery to NO production attenuation will be measured.
Specific aims of investigation
The role of NF-κB antagonists in the regulation of pulmonary tone following exposure to an NO generator
The role of iNOS inhibitors in regulating vascular tone following exposure to an NO generator
Explore pulmonary tone under normoxic and hypoxic conditions, following exposure to an NO generator
The role of the rat pulmonary artery vascular endothelium and eNOS in regulating vascular smooth muscle tone following smoke injury following application of a specific iNOS inhibitor and exposure to an NO generator
There is no difference in pulmonary vascular tone between those arteries treated with an NF-kB antagonist and controls following exposure to an NO generator.
There is no difference in pulmonary vascular tone between controls and those administered a specific iNOS inhibitor.
There is no difference in pulmonary response to the NO generator under normoxic and hypoxic conditions
There is no difference in pulmonary vascular tone with intact or removed endothelium following exposure to the NO generator.