Fatal acute respiratory distress syndrome in a patient with paracoccidioidomycosis: first case report

Paracoccidioidomycosis is a systemic mycosis that is usually acquired early in life by inhalation of conidia which convert in the lungs into yeast forms; these in turn trigger an inflammatory process. This mycosis may appear as an acute/subacute form or a chronic, adult form. Acute/subacute presentations can be observed in children and young adults, with the reticuloendothelial system frequently involved but the lungs are usually spared or present with mild clinical or radiological alterations. Acute respiratory distress syndrome (ARDS), an extensive dysfunction of the lungs alveolar-capillary barrier has occasionally been observed in other endemic mycoses such as coccidioidomycosis, cryptococcosis, histoplasmosis and blastomycosis. We describe the first patient with acute paracoccidioidomycosis who developed fatal ARDS accompanied by multiple organ injuries. The basis of the rarity of this entity in patients with paracoccidioidomycosis, as well as the reasons that may have lead to the development of ARDS in this patient are discussed.

Microcirculatory effects of local and remote ischemic preconditioning in supraceliac aortic clamping

Introduction: Supraceliac aortic clamping in major vascular procedures promotes splanchnic ischemia and reperfusion (I/R) injury that may induce endothelial dysfunction, widespread inflammation, multiorgan dysfunction, and death. We tested the hypothesis that local or remote ischemic preconditioning (IPC) may be protective against injury after supraceliac aortic clamping through the modulation of mesenteric leukocyte-endothelial interactions, as evaluated with intravital microscopy and expression of adhesion molecules. Methods: Fifty-six male Wistar rats (weight, 190 to 250 g), were divided into four groups of 14 rats each: control sham surgery without aortic occlusion; I/R through supraceliac aortic occlusion for 20 minutes, followed by 120 minutes of reperfusion; local IPC through supraceliac aortic occlusion for two cycles of 5 minutes of ischemia and 5 minutes of reperfusion, followed by the same protocol of the IR group; remote IPC through infrarenal aortic occlusion for two cycles of 10 minutes of ischemia and 10 minutes of reperfusion, followed by the same protocol of the IR group. Seven animals per group were used to evaluate in vivo leukocyte-endothelial interactions in postcapillary venules with intravital microscopy and another seven animals per group were used to collect mesentery samples for inmmnohistochemistry demonstration of adhesion molecules expression. Results: Supraceliac aortic occlusion increased the number of rolling leukocytes with slower velocities and increased the number of adherent leukocytes to the venular surface and leukocyte migration to the interstitium. The expression of P-selectin, E-selectin, and intercellular adhesion molecule-1 was also increased significantly after I/R. Local or remote IPC reduced the leukocyte recruitment in vivo and normalized the expression of adhesion molecules. Conclusions: Local or remote IPC reduces endothelial dysfunction on mesenteric microcirculation caused by I/R injury after supraceliac aortic clamping. (J Vase Surg 2010;52:1321-9.) Clinical Relevance: The present study demonstrates that ischemia and reperfusion injury induced by supraceliac aortic occlusion promotes endothelial dysfunction and leukocyte recruitment on mesenteric microcirculation. Local and remote preconditioning reduced leukocyte-endothelial interactions and normalized the expression of endothelial adhesion molecules involved in this process. Although we recognize the limitation of an experimental model, our findings suggest that local and remote ischemic preconditioning minimize the endothelial dysfunction and leukocyte recruitment events that play a central role in systemic inflammation and multiorgan dysfunction after major aortic reconstructions.

Timing-dependent protection of hypertonic saline solution administration in experimental liver ischemia/reperfusion injury

Background. Diving liver ischemia, the decrease in mitochondrial energy causes cellular damage that is aggravated after reperfusion. This injury can trigger a systemic inflammatory syndrome, also producing remote organ damage. Several substances have been employed to decrease this inflammatory response during liver transplantation, liver resections, and hypovolemic shock. The aim of this study was to evaluate the effects of hypertonic saline solution and the best timing of administration to prevent organ injury during experimental liver ischemia/reperfusion. Methods. Rats underwent 1 hr of warm liver ischemia followed by reperfusion. Eighty-four rats Were allocated into 6 groups: sham group, control of ischemia group) (C), pre-ischemia treated NaCl 0.9% (ISS) and NaCl 7.5% (HTS) groups, pre-repefusion ISS, and HTS groups. Blood and tissue samples were collected 4 hr after reperfusion. Results. HTS showed beneficial effects in prevention of live ischemia/reperfusion injury. HTS groups developed increases in AST and ALT levels that were significantly less than ISS groups; however, the HTS pre-reperfusion group showed levels significantly less than the HTS pre-ischemia group. No differences in IL-6 and IL-10 levels, were observed. A significant decrease in mitochondrial dysfunction as well as hepatic edema was observed in the HTS pre-reperfusion group. Pulmonary vascular permeability Was significantly less in the pre-reperfusion HTS group compared to the ISS group. No differences in myeloperoxidase activity were observed. The liver histologic score was significantly less in the pre-reperfusion HTS group compared to the pre-ischemia I-ITS group. Conclusion. HTS ameliorated local and systemic injuries in experimental liver ischemia/reperfusion. Infusion of HTS in the pre-reperfusion period may be an important adjunct to accomplish the best results. (Surgery 2010;147:415-23.)

Neuropeptide Y in Rat Spiral Ganglion Neurons and Inner Hair Cells of Organ of Corti and Effects of a Nontraumatic Acoustic Stimulation

Neuropeptide Y (NPY) is an important neuromodulator found in central and peripheral neurons. NPY was investigated in the peripheral auditory pathway of conventional housed rats and after nontraumatic sound stimulation in order to localize the molecule and also to describe its response to sound stimulus. Rats from the stimulation experiment were housed in monitored sound-proofed rooms. Stimulated animals received sound stimuli (pure tone bursts of 8 kHz, 50 ms duration presented at a rate of 2 per second) at an intensity of 80 dB sound pressure level for 1 hr per day during 7 days. After euthanizing, rat cochleae were processed for one-color immunohistochemistry. The NPY immunoreactivity was detected in inner hair cells (IHC) and also in pillar and Deiters` cells of organ of Corti, and in the spiral ganglion putative type I (1,009 m3) and type II (225 m3) neurons. Outer hair cells (OHC) showed light immunoreaction product. Quantitative microdensitometry showed strong and moderate immunoreactions in IHC and spiral ganglion neurons, respectively, without differences among cochlear turns. One week of acoustic stimulation was not able to induce changes in the NPY immunoreactivity intensity in the IHC of cochlea. However, stimulated rats showed an overall increase in the number of putative type I and type II NPY immunoreactive spiral ganglion neurons with strong, moderate, and weak immunolabeling. Localization and responses of NPY to acoustic stimulus suggest an involvement of the neuropeptide in the neuromodulation of afferent transmission in the rat peripheral auditory pathway.

Autoimmunity in IgA deficiency: Revisiting the role of IgA as a silent housekeeper

Both systemic and organ-specific autoimmune diseases are major manifestations of IgA deficiency (IgAD), the most common primary immunodeficiency. In addition, to discuss the clinical findings of IgAD patients, we proposed a hypothesis to explain the high association with autoimmune phenomena. Based on observations, interactions of monomeric IgA with Fc alpha RI result in a partial phosphorylation of FcR gamma-associated FcaRI, notably in the immunoreceptor tyrosine-based activation motif (ITAM) inducing the recruitment of the SHP-1 tyrosine phosphatase. This leads to deactivation of several activating pathways of the immune system including immunoreceptors that bear ITAM motif and ITAM-independent receptors. Consequently, inflammatory reactions and auto-immune process would be prevented.

The outer wall of small airways is a major site of remodeling in fatal asthma

Background: Structural and inflammatory changes in asthma involve both the large and small airways, with involvement of the distal lung being related to disease severity. We have previously shown that changes in the extracellular matrix (ECM) composition of the distal lung are associated with loss of alveolar attachments in patients with fatal asthma. However, major ECM elements, such as collagen I and fibronectin and their regulators, have not been addressed at the distal level. Objective: We sought to evaluate ECM remodeling in the distal lungs of asthmatic patients. Methods: Using immunohistochemistry and image analysis, we determined the content of collagen I and III, fibronectin, and matrix metalloproteinases; (MMPs) 1, 2, and 9 and tissue inhibitors of metalloproteinase (MMPs) 1 and 2 in the large and small airways and lung parenchyma of 24 patients with fatal asthma and compared the results with those of 11 nonasthmatic control subjects. Protein content was defined as the area of positive staining divided by basement membrane or septum length. Results: We observed increased collagen I and decreased collagen III content in the small airways of asthmatic patients compared with that seen in control subjects. Greater fibronectin and MMP-1, MMP-2, and MMP-9 content was observed at the outer area of the small airways in asthmatic patients. NIMP content was also increased in the peribronchiolar parenchyma in asthmatic patients. In contrast, TIMP expression was only increased in the large airways of asthmatic patients compared with that seen in control subjects. Conclusions: The outer area of the small airways is a major site of ECM remodeling in fatal asthma, potentially contributing to functional changes and the loss of airway-parenchyma interdependence observed in patients with fatal asthma. (J Allergy Clin Immunol 2009;123:1090-7.)

Early short-term versus prolonged low-dose methylprednisolone therapy in acute lung injury

The present study compared the effects of early short-term with prolonged low-dose corticosteroid therapy in acute lung injury (ALI). In total, 120 BALB/c mice were randomly divided into five groups. In the control group, saline was intratracheally (i.t.) instilled. In the ALI group, mice received Escherichia coli lipopolysaccharide (10 mu g i.t.). ALI animals were further randomised into four subgroups to receive saline (0.1 mL i.v.) or methylprednisolone (2 mg center dot kg(-1) i.v.) at 6 h, 24 h or daily (for 7 days, beginning at day 1). At 1, 3 and 8 weeks, in vivo and in vitro lung mechanics and histology (light and electron microscopy), collagen and elastic fibre content, cytokines in bronchoalveolar lavage fluid and the expression of matrix metalloproteinase (MMP)-9 and -2 were measured. In vivo (static elastance and viscoelastic pressure) and in vitro (tissue elastance and resistance) lung mechanics, alveolar collapse, cell infiltration, collagen and elastic fibre content and the expression of MMP-9 and MMP-2 were increased in ALI at 1 week. Methylprednisolone led to a complete resolution of lung mechanics, avoided fibroelastogenesis and the increase in the expression of MMP-9 and MMP-2 independent of steroid treatment design. Thus, early short-term, low-dose methylprednisolone is as effective as prolonged therapy in acute lung injury.

Inducible nitric oxide synthase inhibition attenuates lung tissue responsiveness and remodeling in a model of chronic pulmonary inflammation in guinea pigs

We evaluated the influence of iNOS-derived NO on the mechanics, inflammatory, and remodeling process in peripheral lung parenchyma of guinea pigs with chronic pulmonary allergic inflammation. Animals treated or not with 1400W were submitted to seven exposures of ovalbumin in increasing doses. Seventy-two hours after the 7th inhalation, lung strips were suspended in a Krebs organ bath, and tissue resistance and elastance measured at baseline and after ovalbumin challenge. The strips were submitted to histopathological measurements. The ovalbumin-exposed animals showed increased maximal responses of resistance and elastance (p < 0.05), eosinophils counting (p < 0.001), iNOS-positive cells (p < 0.001), collagen and elastic fiber deposition (p < 0.05), actin density (p < 0.05) and 8-iso-PGF2 alpha expression (p < 0.001) in alveolar septa compared to saline-exposed ones. Ovalbumin-exposed animals treated with 1400 W had a significant reduction in lung functional and histopathological findings (p < 0.05). We showed that iNOS-specific inhibition attenuates lung parenchyma constriction, inflammation, and remodeling, suggesting NO-participation in the modulation of the oxidative stress pathway. (C) 2008 Elsevier B.V. All rights reserved.

POLYETHYLENE GLYCOL ADDITION DOES NOT IMPROVE EXOGENOUS SURFACTANT FUNCTION IN AN EXPERIMENTAL MODEL OF MECONIUM ASPIRATION SYNDROME

Meconium (MEC) is a potent inactivator of pulmonary surfactant. The authors studied the effects of polyethylene glycol addition to the exogenous surfactant over the lung mechanics and volumes. Human meconium was administrated to newborn rabbits. Animals were ventilated for 20 minutes and dynamic compliance, ventilatory pressure, and tidal volume were recorded. Animals were randomized into 3 study groups: MEC group (without surfactant therapy); S100 group (100 mg/kg surfactant); and PEG group (100 mg/kg porcine surfactant plus 5% PEG). After ventilation, a pulmonary pressure-volume curve was built. Histological analysis was carried out to calculate the mean alveolar size (Lm) and the distortion index (DI). Both groups treated with surfactant showed higher values of dynamic pulmonary compliance and lower ventilatory pressure, compared with the MEC group (P .05). S100 group had a larger maximum lung volume, V30, compared with the MEC group (P .05). Lm and DI values were smaller in the groups treated with surfactant than in the MEC group (P .05). No differences were observed between the S100 and PEG groups. Animals treated with surfactant showed significant improvement in pulmonary function as compared to nontreated animals. PEG added to exogenous surfactant did not improve lung mechanics or volumes.

Autopsy-Proven Determinants of Immediate Fire Death in Lungs

In immediate fire deaths, pulmonary injury may be the main source of mortality, being important to document the histologic findings for the purpose of excluding other modes of death, such as from asphyxia with no gross findings. In this context, a group of morphologic determinants have been targeted with useful makers of pulmonary injury. To facilitate the determination of whether an individual was deceased before the start of a fire and validate the importance of parenchymal alterations in pulmonary injury in fire deaths, we studied lungs in victims of fire (N = 28) and suffocation (N = 40), creating a mathematical model using cluster analysis. For this purpose, a semiquantitative analysis of the distal parenchyma was performed to evaluate the amount of bronchiolar dilatation, overinsufflation (ductal and alveolar), collapse (ductal and alveolar), passive congestion, alveolar edema, and hemorrhage (interstitial and alveolar). These 7 histologic determinants were useful to discriminate fire (bronchiolar dilatation, ductal overinsuflation, alveolar overinsuflation, alveolar hemorrhage) from suffocation lung injuries (alveolar collapse, congestion, and edema). We conclude that these determinants should be included in the routine of forensic pathology.

Immunophenotyping and remodeling process in small airways of idiopathic interstitial pneumonias: functional and prognostic significance

Background and Aims: To test whether different degrees of immunologic and fibrotic airway remodeling processes occur in idiopathic interstitial pneumonias (IIPs), with impact on functional tests and survival, we studied the collagen/elastic system and immune cell density in the bronchiolar interstitium of lungs with the major types of IIPs. Materials and Methods: Histochemistry, immunohistochemistry and morphometric analysis were used to evaluate collagen/elastic fibers and immune cells in the bronchiolar interstitium of open lung biopsies of patients with cryptogenic organizing pneumonia [COP/organizing pneumonia (OP) = 10], acute interstitial pneumonia [AIP/diffuse alveolar damage (DAD) = 20], nonspecific interstitial pneumonia (NSIP/NSIP = 20) and idiopathic pulmonary fibrosis/usual interstitial pneumonia (UIP) = 20. Results: OP lungs presented a significant increase in collagenous/elastic fibers and in the total density of immune cells in the bronchiolar interstitium compared to controls, DAD, NSIP and UIP. We observed a significant increase in CD4, CD8 and CD20 lymphocytes, as well as in neutrophils, macrophages and plasma cells in OP. The increased amount of elastic fibers in the bronchiolar interstitium from OP lungs has a direct association with forced vital capacity (FVC) (r(s) = 0.99, P = 0.03). The most important survival predictor was CD20+ lymphocytes in the bronchiolar interstitium. In decreasing order, patients with UIP [Odds Ratio (OR) = 35.01], high forced expiratory volume in 1 s (FEV1)/FVC FVC (OR = 7.01), increased CD20+ lymphocytes (OR = 4.44) and collagenous/elastic fiber densities (OR = 2.03 and OR = 1.49, respectively) in the bronchiolar interstitium were those who had the greatest risk of death, followed by those with AIP, NSIP and COP. Conclusion: Different degrees of immunologic and fibroelastotic airway remodeling processes occur in the major types of IIPs with impact on physiological tests and survival.

Comparative respiratory toxicity of particles produced by traffic and sugar cane burning

The impact of particle emissions by biomass burning is increasing throughout the world. We explored the toxicity of particulate matter produced by sugar cane burning and compared these effects with equivalent mass of traffic-derived particles. For this purpose, BALB/c mice received a single intranasal instillation of either distilled water (C) or total suspended particles (15 mu g) from an urban area (SP group) or biomass burning-derived particles (Bio group). Lung mechanical parameters (total, resistive and viscoelastic pressures, static elastance, and elastic component of viscoelasticity) and histology were analyzed 24h after instillation. Trace elements and polycyclic aromatic hydrocarbons (PAHs) metabolites of the two sources of particles were determined. All mechanical parameters increased similarly in both pollution groups compared with control, except airway resistive pressure, which increased only in Bio. Both exposed groups showed significantly higher fraction area of alveolar collapse, and influx of polymorphonuclear cells in lung parenchyma than C. The composition analysis of total suspended particles showed higher concentrations of PAHs and lower concentration of metals in traffic than in biomass burning-derived particles. In conclusion, we demonstrated that a single low dose of ambient particles, produced by traffic and sugar cane burning, induced significant alterations in pulmonary mechanics and lung histology in mice. Parenchymal changes were similar after exposure to both particle sources, whereas airway mechanics was more affected by biomass-derived particles. Our results indicate that biomass particles were at least as toxic as those produced by traffic. (C) 2008 Elsevier Inc. All rights reserved.

Arterial and interstitial remodelling processes in non-specific interstitial pneumonia: systemic sclerosis versus idiopathic

Aims: To compare septal and vascular matrix remodelling, vascular occlusion, Pulmonary function tests and survival between two groups: one with idiopathic non-specific interstitial pneumonia (NSIP) and one with NSIP associated with systemic sclerosis (SSc). Methods and results: Pulmonary biopsy specimens were examined from 40 patients, 22 with NSIP and 18 with NSIP associated with SSc. The content of septal collagen and elastic fibres, as well as the elastic fibres in the vascular interstitium, were higher in the SSc group (P = 0.01, P = 0.001 and P < 0.0001, respectively). Among pulmonary function tests. the diffusing capacity for carbon monoxide/alveolar volume was affected to a greater extent in the SSc group (59%) of the predicted value in SSc and 97% in the idiopathic group). There were no differences in collagen content of the vascular interstitium, arterial occlusion, or survival between the two groups. Conclusions: Although the fibrotic process is more intense in the SSc group. it, does not affect the prognosis of these patients. Because the elastotic process is higher in the SSc group, this might suggest that autoimmune inflammatory mechanisms affecting the elastic fibre system play a greater role in the pathogenesis and pulmonary remodelling process of SSc NSIP than in idiopathic NSIP.

Oral tolerance attenuates changes in in vitro lung tissue mechanics and extracellular matrix remodeling induced by chronic allergic inflammation in guinea pigs

Oral tolerance attenuates changes in in vitro lung tissue mechanics and extracellular matrix remodeling induced by chronic allergic inflammation in guinea pigs. J Appl Physiol 104: 1778-1785, 2008. First published April 3, 2008; doi:10.1152/japplphysiol.00830.2007.-Recent studies emphasize the presence of alveolar tissue inflammation in asthma. Immunotherapy has been considered a possible therapeutic strategy for asthma, and its effect on lung tissue had not been previously investigated. Measurements of lung tissue resistance and elastance were obtained before and after both ovalbumin and acetylcholine challenges. Using morphometry, we assessed eosinophil and smooth muscle cell density, as well as collagen and elastic fiber content, in lung tissue from guinea pigs with chronic pulmonary allergic inflammation. Animals received seven inhalations of ovalbumin (1-5 mg/ml; OVA group) or saline (SAL group) during 4 wk. Oral tolerance (OT) was induced by offering ad libitum ovalbumin 2% in sterile drinking water starting with the 1st inhalation (OT1 group) or after the 4th (OT2 group). The ovalbumin-exposed animals presented an increase in baseline and in postchallenge resistance and elastance related to baseline, eosinophil density, and collagen and elastic fiber content in lung tissue compared with controls. Baseline and post-ovalbumin and acetylcholine elastance and resistance, eosinophil density, and collagen and elastic fiber content were attenuated in OT1 and OT2 groups compared with the OVA group. Our results show that inducing oral tolerance attenuates lung tissue mechanics, as well as eosinophilic inflammation and extracellular matrix remodeling induced by chronic inflammation.

Pulmonary morphofunctional effects of mechanical ventilation with high inspiratory air flow

Objective: Uncertainties about the numerous degrees of freedom in ventilator settings leave many unanswered questions about the biophysical determinants of lung injury. We investigated whether mechanical ventilation with high air flow could yield lung mechanical stress even in normal animals. Design. Prospective, randomized, controlled experimental study. Setting: University research laboratory. Subjects. Thirty normal male Wistar rats (180-230 g). Interventions: Rats were ventilated for 2 hrs with tidal volume of 10 mL/kg and either with normal inspiratory air flow (V`) of 10 mL/s (F10) or high V` of 30 mL/s (F30). In the control group, animals did not undergo mechanical ventilation. Because high flow led to elevated respiratory rate (200 breaths/min) and airway peak inspiratory pressure (PIP,aw = 17 cm H2O), two additional groups were established to rule out the potential contribution of these variables: a) normal respiratory rate = 100 breaths/min and V` = 30 mL/sec; and b) PIP,aw = 17 cm H2O and V` 10 mL/sec. Measurements and Main Results: Lung mechanics and histology (light and electron microscopy), arterial blood gas analysis, and type III procollagen messenger RNA expression in lung tissue were analyzed. Ultrastructural microscopy was similar in control and F10 groups. High air flow led to increased lung plateau and peak pressures, hypoxemia, alveolar hyperinflation and collapse, pulmonary neutrophilic infiltration, and augmented type III procollagen messenger RNA expression compared with control rats. The reduction of respiratory rate did not modify the morphofunctional behavior observed in the presence of increased air flow. Even though the increase in peak pressure yielded mechanical and histologic changes, type III procollagen messenger RNA expression remained unaltered. Conclusions: Ventilation with high inspiratory air flow may lead to high tensile and shear stresses resulting in lung functional and morphologic compromise and elevation of type III procollagen messenger RNA expression.