The COVID-19 pandemic: a target for surfactant therapy?

Introduction: The dramatic impact of COVID-19 on humans worldwide has initiated an extraordinary search for effective treatment approaches. One of these is the administration of exogenous surfactant, which is being tested in ongoing clinical trials.

Areas Covered: Exogenous surfactant is a life-saving treatment for premature infants with neonatal respiratory distress syndrome.

The 2nd Annual Clinical Scientist Trainee Symposium, August 22, 2017, London, Canada.

Clinician scientists play a critical role in bridging research and clinical practice. Unfortunately, the neglect of research training in medical schools has created clinicians who are unable to translate evidence from literature to practice. Furthermore, the erosion of research training in medical education has resulted in clinicians who lack the skills required for successful scientific investigation.

The Antibacterial and Anti-inflammatory Activity of Chicken Cathelicidin-2 combined with Exogenous Surfactant for the Treatment of Cystic Fibrosis-Associated Pathogens.

Cystic fibrosis (CF) is characterized by recurrent airway infections with antibiotic-resistant bacteria and chronic inflammation. Chicken cathelicin-2 (CATH-2) has been shown to exhibit antimicrobial activity against antibiotic-resistant bacteria and to reduce inflammation. In addition, exogenous pulmonary surfactant has been suggested to enhance pulmonary drug delivery.

Characteristics and outcomes of Canadian MD/PhD program graduates: a cross-sectional survey.

Background: Combined MD/PhD programs provide a structured path for physician-scientist training, but assessment of their success within Canada is limited by a lack of quantitative data. We collected outcomes data for graduates of Canadian MD/PhD programs.

Methods: We developed and implemented a Web-based survey consisting of 41 questions designed to collect outcomes data for Canadian MD/PhD program alumni from 8 Canadian universities who had graduated before September 2015.

A respiratory-gated micro-CT comparison of respiratory patterns in free-breathing and mechanically ventilated rats.

In this study, we aim to quantify the differences in lung metrics measured in free-breathing and mechanically ventilated rodents using respiratory-gated micro-computed tomography. Healthy male Sprague-Dawley rats were anesthetized with ketamine/xylazine and scanned with a retrospective respiratory gating protocol on a GE Locus Ultra micro-CT scanner. Each animal was scanned while free-breathing, then intubated and mechanically ventilated (MV) and rescanned with a standard ventilation protocol (56 bpm, 8 mL/kg and PEEP of 5 cm HO) and again with a ventilation protocol that approximates the free-breathing parameters (88 bpm, 2.

Lung Lavage and Surfactant Replacement During Ex Vivo Lung Perfusion for Treatment of Gastric Acid Aspiration-Induced Donor Lung Injury.

Background: Ex vivo lung perfusion (EVLP) provides opportunities to treat injured donor lungs before transplantation. We investigated whether lung lavage, to eliminate inflammatory inhibitory components, followed by exogenous surfactant replacement, could aid lung recovery and improve post-transplant lung function after gastric aspiration injury.

Methods: Gastric acid aspiration was induced in donor pigs, which were ventilated for 6 hours to develop lung injury.

Lack of matrix metalloproteinase 3 in mouse models of lung injury ameliorates the pulmonary inflammatory response in female but not in male mice.

Background: The acute respiratory distress syndrome (ARDS) is a complex pulmonary disorder in which the local release of cytokines and chemokines appears central to the pathophysiology.

Objective: Based on the known role of matrix metalloproteinase-3 (MMP3) in inflammatory processes, the objective was to examine the role of MMP3 in the pathogenesis of ARDS through the modulation of pulmonary inflammation.

Materials And Methods: Female and male, wild type (MMP3) and knock out (MMP3) mice were exposed to two, clinically relevant models of ARDS including (i) lipopolysaccharide (LPS)-induced lung injury, and (ii) hydrochloric acid-induced lung injury.

A Pilot Randomized Trial Comparing Weaning From Mechanical Ventilation on Pressure Support Versus Proportional Assist Ventilation.

Objectives: Despite protocols incorporating spontaneous breathing trials, 31% of ICU patients experience difficult or prolonged weaning from mechanical ventilation. Nonfatiguing modes such as pressure support ventilation are recommended. Proportional assist ventilation provides assistance in proportion to patient effort, which may optimize weaning.

Pulmonary imaging abnormalities in an adult case of congenital lobar emphysema.

Congenital lobar emphysema is mainly diagnosed in infants, although rare cases are reported in adults. A 20-yr-old female with acute dyspnea, chest pain and left upper lobe (LUL) chest x-ray hyperlucency underwent 3He magnetic resonance imaging (MRI) for ventilation and apparent diffusion coefficient (ADC) measurements, as well as CT for emphysema and airway wall measurements. Forced expiratory volume in 1s, residual volume, and airways-resistance were abnormal, but there was normal carbon-monoxide-diffusing-capacity.

Cholesterol-mediated surfactant dysfunction is mitigated by surfactant protein A.

The ability of pulmonary surfactant to reduce surface tension at the alveolar surface is impaired in various lung diseases. Recent animal studies indicate that elevated levels of cholesterol within surfactant may contribute to its inhibition. It was hypothesized that elevated cholesterol levels within surfactant inhibit human surfactant biophysical function and that these effects can be reversed by surfactant protein A (SP-A).

Differences in hyperpolarized (3) He ventilation imaging after 4 years in adults with cystic fibrosis.

Purpose: To evaluate cystic fibrosis (CF) subjects over 4 years using (3) He magnetic resonance imaging (MRI), pulmonary function tests, and track hospitalization and physician visits.

Materials And Methods: Five CF adults provided written informed consent to an approved protocol and underwent MRI, spirometry, and plethysmography at baseline, 7 days, and 4 ± 1 years later. (3) He MRI ventilation defect percent (VDP) was generated for all subjects and timepoints.

The effects of exogenous surfactant administration on ventilation-induced inflammation in mouse models of lung injury.

Background: Mechanical ventilation (MV) is an essential supportive therapy for acute lung injury (ALI); however it can also contribute to systemic inflammation. Since pulmonary surfactant has anti-inflammatory properties, the aim of the study was to investigate the effect of exogenous surfactant administration on ventilation-induced systemic inflammation.

Methods: Mice were randomized to receive an intra-tracheal instillation of a natural exogenous surfactant preparation (bLES, 50 mg/kg) or no treatment as a control.

Emerging therapies for treatment of acute lung injury and acute respiratory distress syndrome.

In 2007, Bosma et. al provided a comprehensive review of emerging therapies for the acute respiratory distress syndrome (ARDS), a condition which continues to carry a mortality rate of greater than 30%. Over the past several years, the development of novel and effective therapeutic agents for ARDS remains disappointing, and unfortunately, no recent therapeutic interventions have demonstrated a clear benefit.

The biological effects of lung-derived mediators on the liver.

Despite the use of lung-protective mechanical ventilation (MV), the mortality of patients with acute lung injury remains at 30 to 40%, predominantly due to multiorgan failure. The objective of this study was to determine the biological significance of lung-derived mediators on peripheral organ inflammation. The authors utilized an isolated perfused mouse lung model of lipopolysaccharide (LPS)-induced lung inflammation and protective MV to collect lung-derived mediators.

The effect of tidal volume on systemic inflammation in Acid-induced lung injury.

Background: Overwhelming systemic inflammation has been implicated in the progression of acute lung injury (ALI) leading to multiple organ failure (MOF) and death. Previous studies suggest that mechanical ventilation (MV) may be a key mediator of MOF through an upregulation of the systemic inflammatory response.

Objectives: It was the aim of this study to investigate mechanisms whereby mechanical stress induced by different tidal volumes may contribute to the development of systemic inflammation and maladaptive peripheral organ responses in the setting of ALI.

Recombinant surfactant protein C-based surfactant for patients with severe direct lung injury.

Rationale: Patients with acute lung injury have impaired function of the lung surfactant system. Prior clinical trials have shown that treatment with exogenous recombinant surfactant protein C (rSP-C)-based surfactant results in improvement in blood oxygenation and have suggested that treatment of patients with severe direct lung injury may decrease mortality.

Objectives: Determine the clinical benefit of administering an rSP-C-based synthetic surfactant to patients with severe direct lung injury due to pneumonia or aspiration.

Surfactant protein-A reduces translocation of mediators from the lung into the circulation.

The objective of this study was to characterize a mouse model of lung inflammation and determine the effect of surfactant protein A (SP-A, or sftpa) on the transfer of inflammatory mediators from these injured lungs into the systemic circulation. Lung inflammation was induced in either sftpa-deficient (-/-) or wild-type (+/+) spontaneously breathing, adult mice via intranasal lipopolysaccharide (LPS). Four hours later, lungs were isolated, perfused, and mechanically ventilated for 2 hours.

Pharmacotherapy for prevention and treatment of acute respiratory distress syndrome: current and experimental approaches.

The acute respiratory distress syndrome (ARDS) arises from direct and indirect injury to the lungs and results in a life-threatening form of respiratory failure in a heterogeneous, critically ill patient population. Critical care technologies used to support patients with ARDS, including strategies for mechanical ventilation, have resulted in improved outcomes in the last decade. However, there is still a need for effective pharmacotherapies to treat ARDS, as mortality rates remain high.

High-frequency oscillation and surfactant treatment in an acid aspiration model.

Both exogenous surfactant therapy and high-frequency oscillation (HFO) have been proposed as clinical interventions in acute respiratory distress syndrome (ARDS). The combination of these 2 interventions has not been studied in a relevant model of ARDS. It was hypothesized that surfactant treatment combined with HFO is superior to either surfactant treatment or HFO alone in a model of ARDS.

Role of cholesterol in the biophysical dysfunction of surfactant in ventilator-induced lung injury.

Mechanical ventilation may lead to an impairment of the endogenous surfactant system, which is one of the mechanisms by which this intervention contributes to the progression of acute lung injury. The most extensively studied mechanism of surfactant dysfunction is serum protein inhibition. However, recent studies indicate that hydrophobic components of surfactant may also contribute.

Elevated endogenous surfactant reduces inflammation in an acute lung injury model.

Acute lung injury (ALI) is associated with severe pulmonary inflammation and alterations to surfactant, and often results in overwhelming systemic inflammation, leading to multiple organ failure. The objective of this study was to determine the effect of increased endogenous surfactant pools on pulmonary and systemic inflammation in a model of lipopolysaccharide (LPS)-induced ALI. Mice received an instillation of liposome-encapsulated (i) dichloromethylene diphosphonic acid (DMDP) to increase surfactant pools via depletion of alveolar macrophages, or (ii) phosphate-buffered saline (PBS).

The effects of hyperoxia exposure on lung function and pulmonary surfactant in a rat model of acute lung injury.

The objective of this study was to determine if prolonged hyperoxia exposure would deplete antioxidants, resulting in excessive oxidative stress that would lead to oxidation of pulmonary surfactant and contribute to lung dysfunction. Rats were exposed to either hyperoxic (> 95% O(2)) or normoxic (21% O(2)) oxygen concentrations for 48 or 60 hours. Pulmonary compliance, inflammatory cells, and total protein levels were measured as indicators of lung injury.

A Search for subgroups of patients with ARDS who may benefit from surfactant replacement therapy: a pooled analysis of five studies with recombinant surfactant protein-C surfactant (Venticute).

Background: Studies to date have shown no survival benefit for the use of exogenous surfactant to treat patients with the ARDS. To identify specific patient subgroups for future study, we performed an exploratory post hoc analysis of clinical trials of recombinant surfactant protein-C (rSP-C) surfactant (Venticute; Nycomed GmbH; Konstanz, Germany).

Methods: We performed a pooled analysis of all five multicenter studies in which patients with ARDS due to various predisposing events were treated with rSP-C surfactant.

The effects of long-term conventional mechanical ventilation on the lungs of adult rats.

Background: Ventilation-induced lung injury is often studied in animal models by using ventilation strategies with high-tidal volumes and high-oxygen concentration over a relatively short period of time. The injury induced by these ventilation strategies includes alterations to the surfactant system and up-regulation of inflammatory markers. Whether these responses to ventilation occur with more clinically relevant ventilation strategies is not known.

Alterations to surfactant precede physiological deterioration during high tidal volume ventilation.

Lung injury due to mechanical ventilation is associated with an impairment of endogenous surfactant. It is unknown whether this impairment is a consequence of or an active contributor to the development and progression of lung injury. To investigate this issue, the present study addressed three questions: Do alterations to surfactant precede physiological lung dysfunction during mechanical ventilation? Which components are responsible for surfactant's biophysical dysfunction? Does exogenous surfactant supplementation offer a physiological benefit in ventilation-induced lung injury? Adult rats were exposed to either a low-stretch [tidal volume (Vt) = 8 ml/kg, positive end-expiratory pressure (PEEP) = 5 cmH2O, respiratory rate (RR) = 54-56 breaths/min (bpm), fractional inspired oxygen (Fi(O2)) = 1.