Treatment of acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), remain unsolved problems of intensive care medicine. ALI/ARDS are characterized by lung edema due to increased permeability of the alveolar-capillary barrier and subsequent impairment of arterial oxygenation. Lung edema, endothelial and epithelial injury are accompanied by an influx of neutrophils into the interstitium and broncheoalveolar space. Hence, activation and recruitment of neutrophils are regarded to play a key role in progression of ALI/ARDS. Neutrophils are the first cells to be recruited to the site of inflammation and have a potent antimicrobial armour that includes oxidants, proteinases and cationic peptides. Under pathological circumstances, however, unregulated release of these microbicidal compounds into the extracellular space paradoxically can damage host tissues. This review focuses on the mechanisms of neutrophil recruitment into the lung and on the contribution of neutrophils to tissue damage in ALI.

Contribution of neutrophils to acute lung injury.

Pulmonary injury from smoke inhalation is common in burn victims, significantly contributing to the morbidity and mortality of fire-related injuries. The impacts of improvement in other aspects of burn care have not been mirrored in treatment of smoke inhalation. Smoke is heterogeneous and unique to each fire; it comprises particulates, respiratory irritants and systemic toxins as well as heat, all contributing to the pathological insult. Thermal injury below the vocal cords is rare because of effective heat dissipation in the upper airway. Particulate matter is the chief contributor to the pathophysiology of smoke inhalation injury, which has been extensively described. Of paramount importance is the cascade of inflammatory mediators following interaction of irritant substances with lung parenchyma, leading to pulmonary oedema, cast formation, airway obstruction, loss of hypoxic pulmonary vasoconstriction and ventilation/perfusion mismatch. Current treatment is based on supportive care, with airway management, mechanical ventilation, humidification and aggressive airway toilet the mainstays. Nebulisation of n2-agonists, heparin and N-acetylcysteine have a role in management, as does more specific treatment of carbon monoxide or cyanide intoxication. Many promising treatments are currently under investigation. The therapeutic strategy of decontaminating the lungs early after smoke exposure to prevent inhalation injury has received little attention and may be of significant value. This could potentially utilise amphoteric, hypertonic chelating agents developed for topical and ocular chemical exposures.

Management of acute smoke inhalation injury

The pulmonary endothelium is a metabolically active continuous monolayer of squamous endothelial cells that internally lines blood vessels and mediates key processes involved in lung homoeostasis. Many of these processes are disrupted in acute respiratory distress syndrome (ARDS), which is marked among others by diffuse endothelial injury, intense activation of the coagulation system and increased capillary permeability. Most commonly occurring in the setting of sepsis, ARDS is a devastating illness, associated with increased morbidity and mortality and no effective pharmacological treatment. Endothelial cell damage has an important role in the pathogenesis of ARDS and several biomarkers of endothelial damage have been tested in determining prognosis. By further understanding the endothelial pathobiology, development of endothelial-specific therapeutics might arise. In this review, we will discuss the underlying pathology of endothelial dysfunction leading to ARDS and emerging therapies. Furthermore, we will present a brief overview demonstrating that endotheliopathy is an important feature of hospitalised patients with coronavirus disease-19 (COVID-19).

Endothelial Damage in Acute Respiratory Distress Syndrome.

Neutrophil Recruitment: From Model Systems to Tissue-Specific Patterns.

EVOLUTION OF THE FIELD Until surprisingly recently, burn care was a depressing field, in which terrible suffering and tragic outcomes were the general expectation. Patients died after burning from burn shock during the first few postinjury days. If they survived this period, death came from wound sepsis during the first few postinjury weeks. Respiratory insufficiency killed those who escaped these two most common problems. These issues were understood poorly, if at all, in the early part of the 20th century. The casualties of disastrous accidents and wars promoted innovation in burns. Clinical observations of victims of the Rialto Concert Hall fire in 1930 and the Coconut Grove fire in 1942 made surgeons aware of the vastly increased fluid requirements of burn patients during the first 1 to 2 days after injury. This led to the development of the Moore Burn Budget Formula. At the end of World War II, stimulated by burn injuries seen in armored and aerial warfare and in the fire bombings of cities, the United States Army Institute of Surgical Research was established to ensure an adequate understanding of burn injury on which to base the management of future casualties. This group refined clinical observations and developed weightand burn size based resuscitation formulas, such as the Evans, Brooke, and modified Brooke. In the early 20th century, burn wounds were managed by application of any number of topical preparations. Septic death was still the lot of most patients with large injuries. In the 1970s, early excision of small deep burns and immediate autografting was reported to result in shortened hospital stays, reduced patient suffering, and better functional outcomes. To do these operations in patients with larger injuries, particularly children, surgeons required sophisticated intensive care and blood banking technologies that were then in their infancies. But surgeons, notably at the Army Institute of Surgical Research and at the Massachusetts General Hospital, were successful in exploring these strategies in patients with large wounds. They demonstrated improved survival in patients with burns that were previously routinely lethal. These operations have evolved over the intervening years, so that near total early excision is now possible and patients with very large wounds have excellent survival probabilities. Respiratory failure, induced by inhalation injury or by systemic inflammation is the final common killer of burn patients who follow the natural history of their injuries. Development of positive pressure ventilation, lung protective ventilation strategies, general critical care techniques, and innovative modes of support have contributed to markedly enhanced survival in these patients, but respiratory failure remains a serious problem in the burn intensive care unit. Although burn injury continues to cause great suffering, survival and outcomes quality have steadily imReceived November 10, 2003; Accepted November 10, 2003. From the Burn Surgery Service, Shriners Hospital for Children, Department of Surgery, Division of Burns and Trauma, Massachusetts General Hospital; Department of Surgery, Harvard Medical School, Boston, MA. Correspondence address: R L Sheridan, MD, Shriners Hospital for Children, 51 Blossom St, Boston, MA 02114.

What's new in burns and metabolism.

Studies have suggested that ET-1 (endothelin-1) is associated with lung injury, airway inflammation and increased vascular permeability. In the present study we have tested the hypothesis that treatment with a dual ET-1 receptor antagonist will decrease airway obstruction and improve pulmonary function in sheep with combined S+B (smoke inhalation and burn) injury. Twelve sheep received S+B injury using the following protocol: six sheep were treated with tezosentan, an ETA and ETB receptor antagonist, and six sheep received an equivalent volume of vehicle. Physiological and morphological variables were assessed during the 48 h study period and at the end of the study. There was no statistically significant difference in the PaO2/FiO2 (partial pressure of O2 in arterial blood/fraction of O2 in the inspired gas) ratio of the tezosentan-treated animals compared with controls; however, lung lymph flow was significantly higher (P<0.05) in the treated animals. PVRI (pulmonary vascular resistance index) was significantly reduced (P<0.05) in the tezosentan-treated animals. Assessment of NOx (nitric oxide metabolite) levels in plasma and lymph showed significantly elevated (P<0.05) levels in the tezosentan-treated animals compared with levels in untreated sheep. The degree of bronchial obstruction was similar in both treated and control sheep; however, bronchiolar obstruction was reduced in sheep treated with tezosentan. Histopathologically, no difference in the degree of parenchymal injury was detected. In conclusion, administration of a dual ET-1 receptor antagonist prevented an increase in PVRI after injury and reduced the degree of bronchiolar obstruction in sheep with S+B; however, treated sheep showed higher levels of NOx and increased lung lymph flow. Tezosentan treatment was ineffective in protecting against acute lung injury in this model.

Effects of a dual endothelin-1 receptor antagonist on airway obstruction and acute lung injury in sheep following smoke inhalation and burn injury

Accumulation of neutrophils in the lung contributes to the endothelial damage in the tissue associated with acute respiratory distress syndrome. This initial recruitment of neutrophils within the pulmonary microvasculature may involve P-selectin. Thus we hypothesized that an antibody against P-selectin would reduce pulmonary damage. Sheep were chronically instrumented and prepared. The first group received 40% body surface area third-degree burns with 48 breaths of cotton smoke and 1 mg/kg of anti-(P-selectin) antibody (termed 3D4) 1 h post injury (n fl 5). The second group (non-treated) received the same injury but no antibody treatment (n fl 6). The third group comprised of sham animals without any injury or antibody treatment (n fl 6). Sheep were studied for 48 h during which they were uniformly resuscitated with Ringer’s lactate solution by following the Parkland formula. All the animals were mechanically ventilated. In the non-treated injured group, the arterial partial pressure of O2 (‘PaO2’)/inspired fraction of O2 (‘FiO2’) ratio dropped to 168‡30 at 48 h, whereas the lung lymph flow increased to an average of 46‡9 ml/h (10-fold of baseline). These changes were not prevented by an anti-(P-selectin) antibody. The plasma and lymph nitrate/nitrite levels were lower in the antibody-treated group than in the non-treated group. The lymph conjugated dienes were significantly lower in the treated animals. However, lung myeloperoxidase activity and lung tissue conjugated dienes were significantly increased in the treated animals compared with the non-treated injured controls. In conclusion, although the anti-(P-selectin) antibody did not protect against lung injury during the initial 48 h of burn and smoke, it decreased some aspects of injury in the peripheral microcirculation.

P-selectin blockade fails to improve acute lung injury in sheep

Smoke inhalation injury increases the morbidity and mortality of burn patients. Previous studies have shown that an ovine model of cooled cotton smoke inhalation injury and 40% total body surface area cutaneous burn (S+B) models the pathophysiology of these injuries in humans [1]. Initial injury from smoke inhalation is limited to the tracheobronchial airways and is characterized by epithelial cell exfoliation, mucus secretion, increased submucosal microvascular permeability and acute inflammatory cell exudation [2]. These responses promote the formation of obstructive airway casts [3]. Recent studies have shown that a major component of intrapulmonary obstructive material is mucus derived from tracheobronchial glands, and that upper airway obstructive material migrates into distal airways and parenchyma. Obstructive casts are described life threatening, and are considered important in the development of acute lung injury [4]. This study describes morphological changes in bronchial mucous glands in normal sheep and in sheep 48 hours after smoke inhalation and burn (S+B) injury.

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Abhijit Chandra

Papers

Effects of a dual endothelin-1 receptor antagonist on airway obstruction and acute lung injury in sheep following smoke inhalation and burn injury

P-selectin blockade fails to improve acute lung injury in sheep

Morphometric and Ultrastructural Assessment of Bronchial Mucous Glands in Sheep Following Smoke Inhalation and Burn Injury