The Pathophysiology Of Acute Smoke Inhalation Injury Biology Essay


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Burns are the fourth most frequent source of injury-related unintentional death worldwide [1] . Pulmonary complications following acute smoke inhalation (ASI) are significant factors in the high morbidity and mortality seen in the burns patient [2] . Over 50% of fire-associated deaths are due to smoke inhalation [3] , and over 30% of patients who suffer from ASI perish [4] . Furthermore, inhalation injury predisposes the burns patient to pneumonia, increasing mortality risk by 90% [5] . 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 years3. The World Health Organisation states over 100 million people annually develop pulmonary inflammation from fires [6] . 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 [7] . The recent volcanic eruptions in Indonesia compel the necessity to provide effective solutions in treating ASI, with over 100 islanders dying from ash inhalation in November 2010 [8] .

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 [9] . Large amounts of smoke molecules are accrued in the tracheobronchial and parenchymal lung areas, causing severe local and systemic consequences [10] . In this review, the pathophysiology of ASI injury is described in light of current literature, followed by discussion of the existing and potential pharmacological interventions to treat the ASI patient.

The physical and chemical nature of acute inhalation injury

The physical and chemical nature of smoke provides insight into the poor prognosis of ASI victims. Smoke consists of a particulate and gas phase, and the materials under combustion mediate noxious gases released. 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 hydrophilic molecules such as ammonia and hydrogen chloride. Hydrophilic molecules reach the parenchyma via soot particles of <5µm, which provide a surface for hydrophilic compounds to be adsorbed. Hydrophobic compounds reach the lung parenchyma as isolated molecules. Although the majority of burns victims die of acute carbon monoxide poisoning, a significant proportion initially survive yet suffer fatally from pulmonary complications, systemic inflammatory response syndrome (SIRS) and subsequent respiratory failure. These deaths are significant, and intervening in the pathogenesis of pulmonary dysfunction is a potential strategy to improve clinical outcomes.

Carbon monoxide

Carbon monoxide poisoning is responsible for 50% of fire associated mortalities [11] . A colourless, odourless, tasteless gas, carbon monoxide is created from the incomplete combustion of compounds containing carbon atoms. When combining with haemoglobin, carbon monoxide binds with a relative affinity of 270 times greater than oxygen, producing carboxyheamoglobin (COHb) [12] . The dissociation curve of oxyheamoglobin is displaced to the left, impairing the unloading of oxygen. Muscle anoxia occurs by the binding of carbon monoxide to myoglobin [13] . Adenosine triphospahte (ATP) generation falls, ultimately leading to the energetic failure of cells [14] . The clinical diagnosis of carbon monoxide poisoning is complex , and co-oximetry is required to verify CO poisoning [15] .

Hydrogen cyanide (HCN)

A colourless gas, HCN reversibly inhibits cytochrome c , the final oxidase enzyme 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 the range of materials releasing it under combustion and toxic metabolic consequences.

Hydrocarbons in smoke

Smoke contains particles of soot, and a diverse constellation of hydrocarbon molecules. Although heterogeneous in structure, many hydrocarbons are irritant and carcinogenic. High concentrations of aldehydes occur in smoke, such as acrolein, and are NO (nitric oxide) 'generator' molecules. Halogens and nitrogen containing compounds from polymers contribute to parenchymal irritation [16] , [17] . Molecules containing unpaired electrons are abundant in smoke, such as reactive oxygen species (ROS). Polyvinyl chloride, polyethylene and polyurethane release toxic gases including chlorine, hydrocarbons, isocyante, ketones, aldehydes and hydrogen cyanide.

The anatomy and physiology of smoke inhalation injury

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 by afferent signalling and local inflammatory stimulation [18] . Somatic c-fibres in the lung also respond to pulmonary irritation, releasing local inflammatory signals. The neurogenic pathway refers to the stimulation of nerves in somatic tissue suffering from smoke and burn injury. The neurogenic pathway releases local neuropeptides and pro-inflammatory markers such as bradykinin, substance P, calcitonin gene related peptide (CGRP, a potent vasodilator) and angiotensin II [19] . A cytokine 'storm' is created in the respiratory tract, which acts in concert with inhaled toxins to worsen outcome, by encouraging the extravasation of plasma proteins, smooth muscle contraction and mucus production in the tracheobronchial system.

Supra glottic (upper) airways

Kinetic energy 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 tracheobronchial area

The major signalling cascade leading to inflammation in ASI is described below.

Neurogenic stimulation of the conducting airway zone releases a plethora of neuropeptides such as neurokinin-1 and substance P, which are potent bronchoconstrictors. The complement cascade is initiated through local small signal-protein release [20] . The discharge of histamine from resident pulmonary macrophages activates intracellular inflammatory processes. Under these local signals, xanathine oxidase enzyme is transcribed. Xanathine oxidase enzyme synthesises uric acid, an intracellular 'danger signal' [21] . Uric acid initiates NALP3 inflammasome production, which stimulates interleukin release from lymphocytic cells. The inflammatory processes in ASI have positive feedback characteristics, which actually worsen outcomes. For example, airway mast cells and macrophages intensify lung dysfunction by amplifying the production of cytokines in response to both local factors and the irritant constituents of smoke, further contributing to the process of cytokine induced cellular activation and damage [22] .

Released cellular constituents may be either stored in vesicular apparatus or synthesised rapidly at the nuclear level, under the influence of liberated cytosolic transcription factors (discussed in the next section). The interleukins IL1 and IL8 are released in the latter manner from leukocytes, and are chemo-attractant to neutrophils (polymorphonuclear leukocytes). IL derived neutrophil migration and activation initiates an intrinsic oxidative burst which approximates ROS and RNS to the airways and lung parenchyma [23] . The surge in cytokines upregulates iNOS (inducible nitric oxide synthase) enzyme transcription in an array of pulmonary cell types. Downstream reactive species of iNOS such as peroxynitrite, a reactive nitrogen species (RNS) are formed in conjunction with superoxide (O2-). Reactive species from smoke and endogenous inflammatory processes increase pulmonary and bronchial vascular permeability to plasma proteins.

Neutral endopeptidase (NEP), a local regulatory enzyme, is released by lung epithelia and macrophages upon toxic insult. NEP hydrolyses peptide bonds of intercellular cytokines, limiting cellular exposure to cytokines. Interfering with the output effect of the signalling pathway is a vital negative feedback process. Unfortunately, the presence of NEP is transient, due to necrotic sloughing of airway epithelia following toxic insult.

The increase in local endothelial permeability, mass trans-vascular flux of plasma proteins, hyperaemia and vasodilatation in ASI creates pulmonary oedema14-17. When managing burns patients, oedema may be exacerbated by intravenous fluid resuscitation. Although required to treat shock and plasma loss, aggressive fluid management and mechanical ventilation may worsen outcome. This phenomenon is referred to as 'fluid creep' in burns centres [24] . Fluid creep remains a challenge in post burn and ASI care, although recent work suggests colloidal plasma replacement may partly ameliorate filtration of excess fluid [25] . Protein transudation, exfoliation of epithelial cells and excessive mucus secretions obstruct the airways, and where formed, luminal occlusions are referred to as "cast obstructions of the tracheobronchial system" [26] . Tracheobronchial casts impede mechanical ventilation and contribute distal organ hypoxia. High pressure ventilation induces barotrauma to alveoli, another clinical iatrogenicity of vital acute care. The tracheobronchial hallmarks of ASI are increased pulmonary shunt fraction, trans-pulmonary fluid flux and a reduction in the Pa O2:FiO2 (arterial O2:inspired fractional O2 ratio) [27] .

Hyperaemic complications in the ASI injury

Bronchial blood enters the tracheobronchial circulation through bronchio-pulmonary vascular anastamoses. Burns over 30% of total body surface area induce vascular hyperpermeability in the lung parenchyma, intestines and colon, characteristic of the systemic inflammatory response [28] . In an ovine model, ASI increased bronchial blood flow by a factor of 8 [29] . To experimentally limit the hyperaemic response, surgical ligation of the bronchial arteries reduced fluid transudation and the clinical complications of oedema. The hyperaemic response is therefore implicated as a forbearer of 'downstream' clinical complications in ASI.

Hyperaemic blood flow in the lung and intestine is attributed to iNOS formation, NO production and vasodilatation [30] . Sympathetic inflammatory signalling in burns/ASI causes whole system macrocosmic consequences, such as end organ failure [31] . In the intensive care situation, burns and ASI should be regarded as independent but homologous injuries where present [32] .

The lung parenchyma

Transvascular fluid flux, pulmonary shunting, direct alveolar collapse and atelectasis characterize ASI at the level of the lung parenchyma, indicating a generalised condition known as acute lung injury (ALI), in which gaseous exchange is severely impaired [33] . In ASI, the increased concentration of blood NO induces endothelial smooth muscle relaxation, and a subsequent loss of small vessel hypoxic vasoregulation in the lung [34] . The destruction of alveolar surfactant attenuates inspiratory capacity, eventually causing atelectasis and collapse. The chemotactic cytokine storm attracts and activates polymorphonuclear leukocytes, which bind to the alveolar capillary membrane by L-selectin attachment [35] . Neutrophils release RNS and ROS through the endogenous oxidative burst in close proximity to the alveolar membrane, similar to the tracheobronchial tract discussed above [36] . Catastrophic pulmonary cell death and mucus production ensures cellular casts are exuded into the tracheobronchial system, contributing to excessive sputum production in the ASI patient. To review the clinical consequences the inflammatory response: 1) Pulmonary oedema is formed. 2) Fluid creep may occur. 3) Tracheobronchial casts impede luminal diameter. 4) Mucus secretion increases.

Molecular toxicology of smoke induced acute lung injury

Reactive species in acute smoke inhalation injury

ROS are ubiquitous in smoke (Figure 2), and place oxidative stress on the lung airways. Metabolic reactions in cells create reactive oxygen species such as superoxide, a highly reactive molecule generated by 1-5% of the oxygen undergoing single electron transfer in mitochondrial respiration. Under normophysiological concentrations, ROS are controlled by cellular enzymes and antioxidant constituents of the cytosol such as superoxide dismutase (SOD), catalase enzyme (CAT) and glutathione peroxidase (GSH-Px) [37] . Physiological mechanisms controlling ROS are overburdened in the smoke inhalation injury, contributing to ROS induced cellular death. High concentrations of ROS initiate damage to vital cellular apparatus through oxidative reaction with lipids and proteins. Superoxide is physiologically converted by GSH, to H2O2 (hydrogen peroxide). Hydrogen peroxide is further reduced by CAT to H2O and O2, and hydrogen peroxide may undergo fission to create highly reactive hydroxyl radicals (OH). In smoke inhalation injury, ROS may be inhaled or intrinsically generated to activate pro-inflammatory signalling and nuclear transcription pathways.

Release and consequences of Nuclear Factor Kappa Beta (NF-κB).

NF-kB belongs to the 'Rel' group of transcription factor proteins [38] . Quiescent pulmonary cells contain cytosolic NF-κB. Under static conditions NF-kB is a heterotrimeric protein complex, consisting of inhibitory kappa-beta (IκB), and the p50-p65 subunits. Cytokines, ROS and inhaled toxins induce cytosolic release of nuclear factor kappa beta subunits p50-p65, through a signal transduction cascade of phosphorylation and ubiquitinatination of the serine residues of IκB, utilising cAMP and a kinase enzyme, IKK. In the nucleus free NF-kB (p50-p65) binds with cytokine gene promoter sequences to transcribe 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.

Airway cell apoptosis in the smoke inhalation injury is dependent on activation of c-Jun N-terminal Kinase (JNK) activation. The JNK pathway is inhibited by NF-κB signals, crucially saving respiratory cells from apoptotic cell death. NF-kB concomitantly promotes transcription of inhibitory proteins of caspases, another apoptotic family of enzymes [39] . Acrolein, an aldehyde and common component of smoke, is hypothesised to activate the JNK pathway in smoke inhalation [40] . Macrophages and endothelial cells exposed to components of wood smoke were shown to upregulate NF-κB, in a dose dependent manner [41] . Airway epithelia exposed to carbon soot [42] , hypoxia [43] and ROS [44] also upregulate NF-κB. Therefore, pharmacological manipulation of NF-κB and related transcription products is of interest in ASI to modulate pulmonary injury.

The production and consequences of nitric oxide

A soluble gas, NO is a vital physiological signal, central to the endothelial regulation of vascular tone44. A neurotransmitter in inhibitory noradrenergic non cholinergic nerve cells (i-NANC), NO mediates i-NANC induced bronchodilation. NO production is intricately associated with inflammation, physiological regulation and intracellular signalling.

NO interacts with voltage sensitive potassium channels (Kv), for example the KCNQ channel, to induce smooth muscle cell hyperpolarisation-relaxation. Through Kv activation (opening), K+ channel efflux currents are evoked, the membrane hyperpolarises, cGMP is regenerated, and intracellular [Ca2+] is sequestered by the sarcoplasmic reticulum [45] , [46] . In hypoxic conditions (minus excess NO), sarcolemmal Kv channels are inhibited, causing membrane depolarisation. Membrane depolarisation opens voltage gated calcium channels and the increase in [Ca2+]i triggers contraction.

In ASI, NO interrupts this process of hypoxic vasoregulation, by maintaining an efflux of potassium by maintaining a patent Kv channel. The author draws attention to the fact that mechanisms of NO smooth muscle cell hyperpolarisation are yet to be fully determined.

Nitric oxide synthase enzyme (NOS) produces NO via oxidation of the guanidine group of L-arginine, utilising NADPH and O2 as cosubstrates [47] . Three isoforms of NOS exist; two isoforms of NOS are considered constitutive (cNOS denotes isoforms eNOS and nNOS). cNOS maintains a basal level of NO production. Endothelial and neuronal NOS are supplemented by inducible NOS (iNOS). Pro-inflammatory mediators such as cytokines (TNFα, interleukins, leukotrienes), and bacterial components (LPS, endotoxins) provoke type II respiratory pneumocytes to synthesize iNOS mRNA45. Currently, little experimental data supports a major role of cNOS in the pathophysiological pulmonary and intestinal changes seen in ASI, although recent work indicates nNOS inhibition improves pulmonary outcomes in septic models of ASI. The isoform nNOS is not directly upregulated in the lung following ASI, but is induced upon pneumonic or septic complications, such as Pseudomonas aeruingosa colonisation of the lung [48] . This evidence further implicates iNOS as the primary pathophysiological NO generator in ASI. When exposed to Escheria coli lipopolysaccharide, bladder cells upregulate eNOS.

Following burn and smoke inhalation, normophysiological levels of eNOS are critical to endothelial regulation. It is theorized NOS isoform expression follows a temporal course of variation in ASI [49] , and cNOS is proposed to partake a lesser role in ASI induced inflammation than iNOS. There is a paucity of evidence supporting immediate neuronal or endothelial NOS upregulation in ASI injury. The mass induction of iNOS in the lung parenchyma, tracheobronchial system and intestine has grave consequences for the burns patient. 1) NO induces vasodilatation of the pulmonary vasculature. 2) Pulmonary dilatation and hyperaemia allows migration of inflammatory cells deep into the parenchyma and intestinal mucosa, permitting enteral bacteria to enter the systemic system. Consequences of neutrophil migration include mucus production and cast formation in the tracheobronchial tree. 3) Peroxynitrite formation in the lung secondary to surplus ROS and NO further contributes to pulmonary oedema and difficulty ventilating the patient, necrotising epithelial cells via DNA strand fracture and PARP activation (below). To summarise, hospitalisation, intensive care admission, intubation and ventilation of the ASI patient may be attributed to mass NO-induction in the pulmonary system.

Peroxynitrite production

Acute smoke inhalation is associated with high concentrations of NO and superoxide in the respiratory system, either endogenously produced or inhaled. Peroxynitrite is formed in a diffusion limited reaction between NO and superoxide (NO + O2-  ONOO-). A central pathological metabolite in ASI, peroxynitrite is highly cytotoxic and able to covalently modify molecules, membrane lipids, proteins, DNA, inhibit mitochondrial respiratory enzymes and interfere with cell membrane signal transduction pathways [50] , [51] . Peroxynitrite in vivo reduces mitochondrial respiration and decreased intracellular NAD+, contributing to a reduction in cellular energy production. Trans-peroxynitrous acid has been cited as the specific species responsible for DNA damage, causing modification of G-C base pairs [52] (Figure 1). Toxicity of peroxynitrite is likely due to direct oxidative damage to zinc finger, heam group and thiol moieties of molecules. The mass induction of iNOS in ASI is also intimately linked to peroxynitrite formation.

Figure 1. The structure of peroxynitrite.

The cis conformation of peroxynitrite is most stable in the cytosol. Protonation causes a conformational change to the reactive trans state, by the release of a reactive OH* hydroxyl radical and nitrogen dioxide molecule.

Figure 2 (Flow chart: The Pathophysiology of ASI)

Figure 2 (Page 13) details the pathophysiology of ASI. Arrows indicate a stepwise, temporal process.

Orange represents initial steps, red boxes are biochemical steps that may be targeted with drug therapies. Purple boxes are unwanted consequences of ASI. A colour code is provided on page 13.

PARP (Poly-ADP-ribose enzyme)

DNA damage orchestrated by peroxynitrite activates the nuclear enzyme poly-ADP-ribose (PARP) in cell nuclei. A chromatin bound enzyme, PARP ribosylates nuclear DNA via the use of ADP [53] . Under pathophysiological concentrations of peroxynitrite, cellular energy is rapidly diminished via the process of PARP activation and DNA ribosylation [54] . PARP activation causes necrotic cell death through energetic failure of cells. Necrosis of respiratory cells following smoke inhalation injury may be attributed to NO production, ROS generation and inhalation, downstream peroxynitrite formation, which culminate in PARP activation.

Nitric oxide, superoxide and peroxynitrite have been described as 'good' the 'bad' and 'ugly' in the context of smoke inhalation49. The characterisation of NO as 'good' may be misleading, because in the presence of superoxide, conversion to 'ugly' peroxynitrite inevitably occurs.

Current pharmacological interventions in the ASI injury

The clinical foundations of ASI management are effective fluid resuscitation, airway management and inflammatory modulation. Management of ASI is complicated by local oedema, cast formation and the increased risk of pneumonia upon intubation. The nuances of mechanical ventilation are beyond the scope of this work. Below, current and innovative strategies in managing the inflammatory response to ASI are discussed.

β2 Agonist therapy

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, increasing forced expiratory volume [FEV]. Systemic and nebulised β2-agonists reduce airway resistance, improve lung compliance and lower the peak airway pressure. Barotrauma to alveoli secondary to mechanical ventilation is reduced by β2-agonist therapy. β2-agonists also have an anti-inflammatory, antihistaminergic profile and reduce TNF-α transcription, improve mucociliary clearance and endothelial permeability changes. β2 receptor agonists also inhibit promotional iNOS transcription factors such as NF-kB [55] in ASI.

Extravascular oedema clearance is improved in ASI, by intravenous β2 agonist application. Side effects of tachycardia and hypokalemia require adequate monitoring in an acute setting. Overall, β2 agonists are promising future staples of ASI care, being easily obtainable and economic drug choices.


Meta-analysis of randomised controlled trials and cohort studies in ASI indicates corticosteroids are a therapy of choice in treating acute respiratory failure seen in burns patients [56] , [57] . Notably, intravenous corticosteroids in the ASI ameliorate multi-organ failure in late stage lung injury. The mechanism of action of corticosteroids is to dampen inflammatory signalling, by preventing end-stage organ injury at the nuclear transcription level.

Future pharmacological strategies in acute smoke inhalation injury

Data from β2 agonist and corticosteroid treatments suggests future pharmacological interventions will target processes causing the consequences of pulmonary cell death, the inflammatory response and local signalling molecules. Recent by work Hassan and colleague's demonstrated ASI mortality is primarily due to acute respiratory distress opposed to other complications of burn and smoke such as toxic-shock like illness [58] , although the translocation of bacteria from the intestine in ASI is also a significant factor in critical care.

Intercepting the inflammatory cascade

Interleukins, cytokines, toxins in smoke and bacterial lipopolysaccharide activate NF-κB, a nuclear transcription factor of iNOS. The management of NF-kB and related pro-inflammatory factors is of interest in ASI, because the mass induction of NO and peroxynitrite may be prevented (Figure 2, red boxes). In vivo administration of NF-kB antagonists is likely to be double edged because NF-κB is crucial in anti- apoptotic cell pathways. When examining NF-kB interception, mediators of the intracellular JNK and caspase apoptotic routes should also be closely monitored.

Recent work by Shalub and colleagues demonstrated polymorphisms for TNF-α and IL10 predict mortality in burns patients [59] , [60] . Pre-treatment of anti-IL8 in sheep improves pulmonary function by reducing lung tissue permeability, and inhibition of the powerful vasodilator CGRP reduces hyperaemic and dilatory response to ASI in ovine models. Topical interference with MAPK (mitogen activated protein kinase) p38 inhibitors also reduces pulmonary markers of inflammation, modulating peripheral signalling in burn and smoke injury [61] . However, indiscriminate immuno-interference is predicted to produce undesirable sequelae in the patient. Currently, it is unknown if cytokine, neuropeptide or intracellular signal manipulation attenuates iNOS transcription. In this review, a priori, iNOS production is proposed to be limited through abrogation of intracellular signals such as IKK. Cytokines have a cardinal role in the devastating hyperaemic changes to the pulmonary system following ASI. In the future, specific cytokine management might play a large role in controlling local and systemic inflammation in the burns/ASI patient. To translate such treatments from in vitro to intensive care, NOS transcription, NO and peroxynitrite production should be quantified in relation to anti-inflammatory intracellular signalling molecules.

Inhibiting the activity and production of NO

Abolishing NO induction and will predictably improve pulmonary dynamics. iNOS is implicated as the primary source of NO in ASI, opposed to the functional nature of cNOS. Whereas compounds such as aminoguanidine S-methylthiourea are weakly specific to iNOS, precise allosteric inhibitors of iNOS have been synthesised. The molecules BBS-2 and L-N6-(1-lminoetyl)Lysine-5-tetrazole-amide are true allosteric inhibitors of iNOS [62] , [63] . The affinity of BBS-2 to iNOS is 1500 times than that of cNOS,,. These molecules are not yet approved for clinical use in ASI, but demonstrate potential advantages if deployed in ASI management. 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. Such experimental results confirm the role of iNOS in ASI pathology is central, opposed to cNOS. 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. In smoke inhalation injury, the function and temporal expression of eNOS should be discerned. Eliciting the course of NOS isoform expression may enable targeting of the inflammatory response in a protective manner germane to essential NO generation and physiological function.

The interaction of NO with Kv channels, such as the KNCQ channel is a potential method of limiting pulmonary vasodilatation. By antagonising KCNQ, hypo-polarisation of the membrane may be attenuated in ASI (by evoked hyperpolarisation) using a competitive KCNQ blocking agent. The clinical challenge of limiting the hyperaemic dilatory response in the lung could be achieved with KCNQ blockers such as linopirdine and XE991 that would outcompete NO [64] .

To summarise, physiologically compatible NOS inhibitors should be investigated, and the temporal course of NOS isoforms expression in ASI fully determined. NO-Kv channel interaction should also be explored. Initial toxic insult, endothelial regulation and septic complications in ASI injury may then be independently managed.

Scavenging free radicals

N-acetyl cysteine (NAC) and α-tocopherol (the 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. 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 vitamin C. In paediatric cases of ASI, combined therapy using nebulised heparin (antithrombin) and the antioxidant N-acetylcystine improved reintubation rates and ameliorated cast deposition. Heparin, an inhibitor of factor Xa, prevents fibrin formation in the tracheobronchial tree following ASI [65] , [66] . Scavenging reactive molecules by antioxidant administration is a promising future adjunctive therapy for ASI patients. Interdicting excess NO, ROS and peroxynitrite (the good, the bad and the ugly) in acute smoke injury is a viable method of limiting cellular damage, inflammatory signalling, epithelial sloughing, pulmonary dysfunction and the mortal effects of a toxic insult to the airways.

Inhibiting Poly-ADP-ribose (PARP)

PARP induced ATP depletion, pulmonary cell necrosis and epithelial sloughing causes severe clinical ramifications. Specific PARP inhibitors such as 3-amino-benzamide protect cells from oxidant damage and cell death and reduce cytokine expression in acute lung inflammation models,. PARP inhibitors limit the hyperaemic response, vascular permeability and oedema.

Moreover, PARP inhibition may be favourable compared to NOS inhibitors, avoiding the potential downfalls of attenuating NO production. Pathogenic organisms do not encode PARP and the polymorphonuclear generated ROS burst would not be disrupted, thus protecting the lung from invading microorganisms by maintaining antimicrobial peroxynitrite generation. PARP inhibitors preserve endogenous antibiotic cellular defences and reduce sputum production. The pulmonary milieu remains inconducive to pathogenic organisms, and pneumonic complications in ASI are prevented by PARP inhibitors. In summary, ovine models of PARP inhibition show improved airway integrity, reduced epithelial cell death cast formation and the prevention of septic consequences. PARP inhibitors are likely to yield promising clinical applications in smoke inhalation injury. Finally, one should elect to explore treatments that limit intestinal permeability to bacteria following burn and ASI. Therapies discussed above such as the immune-modulators, (PARP inhibitors, anti-IL8 and anti- NF-kB), may have transferrable effects on intestinal physiology, a worthy consideration of any future treatment regimen.


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, and mortality is high. The central dogma of smoke induced respiratory failure is the upregulation of iNOS and cytokines,. Current treatments for ASI are supportive, replacing fluids and managing airway ventilation. Immunomodulation in ASI shows promise as a future therapeutic strategy, through obviation of molecules and signalling along the inflammatory cascade. 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 pro-inflammatory transcription products. Modulation of cytokines, neuropeptides and interleukins has also demonstrated positive results in animal models.

iNOS inhibitors have been investigated and display promising pulmonary outcomes, and cNOS

inhibition may also take a role in ASI management in relation to sepsis. The clinical goals of iNOS inhibition are based upon moderating of the hyperaemic response, reducing vascular permeability and improving pulmonary dynamics. Exploring the role of NOS inhibitors and NF-κB antagonists in ASI pathophysiology is hence a relatively novel and unexplored field. In the future, treatment may intercept specific cytokines, enzymes and signalling in a temporal process. For the 30% of burns patients suffering the dire consequences of ASI, successful treatments cannot be translated to the bedside sooner.

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