Dani-Louise Dixon

Lung injury in acute pancreatitis: Mechanisms underlying augmented secondary injury

Acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS), are common complications of acute pancreatitis (AP). ALI/ARDS contribute to the majority of AP-associated deaths, particularly in the setting of secondary infection. Following secondary pulmonary infection there can be an exacerbation of AP-associated lung injury, greater than the sum of the individual injuries alone. The precise mechanisms underlying this synergism, however, are not known. In this review we discuss the main factors contributing to the development of augmented lung injury following secondary infection during AP and review the established models of AP in regard to the development of associated ALI.

Lower interleukin-8 levels in airway aspirates from breastfed infants with acute bronchiolitis

Dixon D‐L, Griggs KM, Forsyth KD, Bersten AD. Lower interleukin‐8 levels in airway aspirates from breastfed infants with acute bronchiolitis.
Pediatr Allergy Immunol 2010: 21: e691–e696.
© 2010 John Wiley & Sons A/S
Journal compilation

INTRACELLULAR STORAGE OF SURFACTANT AND PROINFLAMMATORY CYTOKINES IN CO-CULTURED ALVEOLAR EPITHELIUM AND MACROPHAGES IN RESPONSE TO INCREASING CO2 AND CYCLIC CELL STRETCH

Cell stretch stimulates both surfactant and cytokine production. The authors proposed that stretch, through these effects, modifies the pathogenesis of lipopolysaccharide-induced acute lung injury (ALI), and that this is CO2 dependent. Rat alveolar type II cells and macrophages were co-cultured with lipopolysaccharide in 5%, 10%, or 20% CO2 ± stretch (30%, 60 cycles/min) for 6 hours. Intracellular TNF-α and IL-6 increased whereas secreted cytokine and surfactant decreased with increasing CO2. Stretch independently increased intracellular TNF-α and decreased IL-6 secretion. Elevated CO2 may therefore diminish secretion of proinflammatory cytokines by alveolar cells, contributing to an explanation for protective hypercapnia in ALI.

L-Arginine–induced acute pancreatitis results in mild lung inflammation without altered respiratory mechanics

ABSTRACT Acute lung injury is a common complication of acute pancreatitis (AP) and contributes to the majority of AP-associated deaths. Although some aspects of AP-induced lung inflammation have been demonstrated, investigation of resultant changes in lung function is limited. The aim of this study was to characterize acute lung injury in L-arginine–induced AP. Seven groups of male Sprague-Dawley rats (n = 4–10/group) received 2 intraperitoneal (i.p.) injections of L-arginine (250 mg/100 g) at 6, 12, 24, 36, 48, or 72 hours before measurement of lung impedance mechanics. Control rats (n = 10) received i.p. saline. Bronchoalveolar lavage (BAL), plasma, and pancreatic and lung tissue were collected to determine pancreatic and lung measures of acute inflammation. AP developed between 6 and 36 hours, as indicated by increased pancreatic abnormal acinar cells, myeloperoxidase (MPO) activity, edema, and plasma amylase activity, before beginning to resolve by 72 hours. In the lung, MPO activity increased (2.4-fold) from 12 hours, followed by a modest increase in lung edema at 48 hours, with increased BAL cell count (2.5-fold) up to 72 hours (P < .05). In contrast, no significant changes in lung mechanics were evident over the same period. Despite measurable lung inflammation, no significant deterioration in respiratory function resulted from L-arginine–induced AP.

Caerulein-induced acute pancreatitis results in mild lung inflammation and altered respiratory mechanics

ABSTRACT Acute lung injury is a common complication of acute pancreatitis (AP) and contributes to the majority of AP-associated deaths. Although some aspects of AP-induced lung inflammation have been demonstrated, investigation of resultant changes in lung function is limited. The aim of this study was to characterize lung injury in caerulein-induced AP. Male Sprague Dawley rats (n = 7–8/group) received 7 injections of caerulein (50 μg/kg) at 12, 24, 48, 72, 96, or 120 hours before measurement of lung impedance mechanics. Bronchoalveolar lavage (BAL), plasma, pancreatic, and lung tissue were collected to determine pancreatic and lung measures of acute inflammation. AP developed between 12 and 24 hours, as indicated by increased plasma amylase activity and pancreatic myeloperoxidase (MPO) activity, edema, and abnormal acinar cells, before beginning to resolve by 48 hours. In the lung, MPO activity peaked at 12 and 96 hours, with BAL cytokine concentrations peaking at 12 hours, followed by lung edema at 24 hours, and BAL cell count at 48 hours. Importantly, no significant changes in BAL protein concentration or arterial blood gas-pH levels were evident over the same period, and only modest changes were observed in respiratory mechanics. Caerulein-induced AP results in minor lung injury, which is not sufficient to allow protein permeability and substantially alter respiratory mechanics.

Neutrophil infiltration and activation in bronchiolitic airways are independent of viral etiology

Hospitalization with bronchiolitis is linked to the development of early childhood chronic wheeze and asthma. Viral etiology and severity of inflammation are potential contributing factors. Previously we observed reduced airway neutrophil infiltration in breastfed bronchiolitic infants, with a corresponding reduction in disease severity. This study aimed to examine whether respiratory viral etiology and co‐infection alters the pattern of neutrophil influx, and the inflammatory mediator profile, resulting in epithelial damage in bronchiolitis.

The heterogeneity of viral bronchiolitis: A lack of universal consensus definitions

Viral bronchiolitis is one of the most common hospital presentations in infancy and as such represents a major healthcare burden worldwide. However despite this, there are currently no effective targeted therapies nor can those infants at highest risk for developing severe disease or subsequent respiratory morbidity be predicted on initial hospital presentation. Current definitions of bronchiolitis in the published literature vary significantly in terms of the age range at presentation, specific clinical symptoms, causative virus, and the inclusion or exclusion of infants with previous presentations and/or various comorbidities. In this review, we highlight how this heterogeneity among definitions contributes to a lack of clarity on this condition and its likely multiple endotypes. We argue that without a new universal consensus definition or sets of definitions, progress into bronchiolitis will continue to be stalled.

Tripeptide feG Prevents and Ameliorates Acute Pancreatitis-Associated Acute Lung Injury in a Rodent Model

BACKGROUND The synthetic tripeptide feG (D-Phe-D-Glu-Gly) is a novel pharmacologic agent that decreases neutrophil recruitment, infiltration, and activation in various animal models of inflammatory disease. We aimed to investigate the effect of feG as both a preventive treatment when administered before acute lung injury and as a therapeutic treatment administered following initiation of acute lung injury. METHODS Lung injury was assessed following prophylactic or therapeutic intratracheal feG administration in a “two-hit” rodent model of acute pancreatitis plus intratracheal lipopolysaccharide. RESULTS Following both prophylactic and therapeutic feG administration, there were significant improvements in arterial blood oxygenation and respiratory mechanics and decreased lung edema, BAL protein concentration, histologic tissue injury scores, BAL cell infiltration, and lung myeloperoxidase activity. Most indices of lung damage were reduced to baseline control values. CONCLUSIONS feG reduced leukocyte infiltration, ameliorated the severity of inflammatory damage, and restored lung function when administered either prophylactically or therapeutically in a two-hit rat model of acute pancreatitis plus intratracheal lipopolysaccharide.

Pulmonary Effects of Chronic Elevation in Microvascular Pressure Differ Between Hypertension and Myocardial Infarct Induced Heart Failure

BACKGROUND Chronic heart failure (CHF) following coronary artery ligation and myocardial infarction in the rat leads to a homeostatic reduction in surface tension with associated alveolar type II cell hyperplasia and increased surfactant content, which functionally compensates for pulmonary collagen deposition and increased tissue stiffness. To differentiate the effects on lung remodelling of the sudden rise in pulmonary microvascular pressure (Pmv) with myocardial infarction from its consequent chronic elevation, we examined a hypertensive model of CHF. METHODS Cardiopulmonary outcomes due to chronic pulmonary capillary hypertension were assessed at six and 15 weeks following abdominal aortic banding (AAB) in the rat. RESULTS At six weeks post-surgery, despite significantly elevated left ventricular end-diastolic pressure, myocardial hypertrophy and increased left ventricular internal circumference in AAB rats compared with sham operated controls (p≤0.003), lung weights and tissue composition remained unchanged, and lung compliance was normal. At 15 weeks post-surgery increased lung oedema was evident in AAB rats (p=0.002) without decreased lung compliance or evidence of tissue remodelling. CONCLUSION Despite chronically elevated Pmv, comparable to that resulting from past myocardial infarction (LVEDP>19mmHg), there is no evidence of pulmonary remodelling in the AAB model of CHF.

Surfactant and lung function following cardiac surgery

Cardio-pulmonary bypass (CPB) is associated with prolonged mechanical ventilation (PMV) in the intensive care unit (ICU), and an increase in morbidity and mortality. Surfactant dysfunction could result in atelectasis and contribute to PMV. However, it is unclear whether cessation of mechanical ventilation, with resultant atelectasis, and the use of a foreign bypass circuit during CPB, would affect the concentration of surfactant constituents and whether this, in turn, is associated with PMV. Pulmonary surfactant, which increases lung compliance and opposes atelectasis by reducing alveolar surface tension, is produced in the lung by alveolar type II cells. It is comprised of 10% protein, predominantly the surfactant proteins A, B, C & D, and 90% phospholipid, which can be separated into large surfactant aggregates (LA) and small surfactant aggregates (SA). LA, the metabolic precursors to SA, are the greatest contributors to reduction of surface tension. In models of acute lung injury, LA are disproportionately converted to SA, resulting in an increased SA:LA ratio. This depletion of LA stores is associated with decreased lung compliance and function. Normal surfactant functioning and production is an important contributor to decreasing atelectasis and the need for PMV. Intra-operative atelectasis, accompanied by inflammation in the alveoli, has been associated with reduced intra-operative gas exchange, and the need for PMV. During CPB, ventilation is often ceased allowing the lungs to collapse to functional residual capacity (FRC) for prolonged periods. In addition, exposure of patient blood to the foreign bypass circuit may