Alexandre Muxfeldt Ab'Saber

Effects of bone marrow-derived mononuclear cells on airway and lung parenchyma remodeling in a murine model of chronic allergic inflammation

We hypothesized that bone marrow-derived mononuclear cells (BMDMC) would attenuate the remodeling process in a chronic allergic inflammation model. C57BL/6 mice were assigned to two groups. In OVA, mice were sensitized and repeatedly challenged with ovalbumin. Control mice (C) received saline under the same protocol. C and OVA were further randomized to receive BMDMC (2 × 10⁶) or saline intravenously 24 h before the first challenge. BMDMC therapy reduced eosinophil infiltration, smooth muscle-specific actin expression, subepithelial fibrosis, and myocyte hypertrophy and hyperplasia, thus causing a decrease in airway hyperresponsiveness and lung mechanical parameters. BMDMC from green fluorescent protein (GFP)-transgenic mice transplanted into GFP-negative mice yielded lower engraftment in OVA. BMDMC increased insulin-like growth factor expression, but reduced interleukin-5, transforming growth factor-β, platelet-derived growth factor, and vascular endothelial growth factor mRNA expression. In conclusion, in the present chronic allergic inflammation model, BMDMC therapy was an effective pre-treatment protocol that potentiated airway epithelial cell repair and prevented inflammatory and remodeling processes.

Sex-specific lung remodeling and inflammation changes in experimental allergic asthma

There is evidence that sex and sex hormones influence the severity of asthma. Airway and lung parenchyma remodeling and the relationship of ultrastructural changes to airway responsiveness and inflammation in male, female, and oophorectomized mice (OVX) were analyzed in experimental chronic allergic asthma. Seventy-two BALB/c mice were randomly divided into three groups (n=24/each): male, female, and OVX mice, whose ovaries were removed 7 days before the start of sensitization. Each group was further randomized to be sensitized and challenged with ovalbumin (OVA) or saline. Twenty-four hours after the last challenge, collagen fiber content in airways and lung parenchyma, the volume proportion of smooth muscle-specific actin in alveolar ducts and terminal bronchiole, the amount of matrix metalloproteinase (MMP)-2 and MMP-9, and the number of eosinophils and interleukin (IL)-4, IL-5, and transforming growth factor (TGF)-β levels in bronchoalveolar lavage fluid were higher in female than male OVA mice. The response of OVX mice was similar to that of males, except that IL-5 remained higher. Nevertheless, after OVA provocation, airway responsiveness to methacholine was higher in males compared with females and OVX mice. In conclusion, sex influenced the remodeling process, but the mechanisms responsible for airway hyperresponsiveness seemed to differ from those related to remodeling.

Protective effects of ascorbic acid pretreatment in a rat model of intestinal ischemia-reperfusion injury: A histomorphometric study

BACKGROUND Ascorbic acid has shown promise in attenuation of intestinal ischemia-reperfusion (I/R) injury. The aim of this study was to determine the protective effects of ascorbic acid on intestinal morphology during IR injury in rats. MATERIALS AND METHODS We examined morphological changes in the small intestine of Wistar rats after (i) 40 minutes of ischemia (I), (ii) ischemia followed by 30 min of reperfusion (IR), (iii) ischemia with ascorbic acid (IA), (iv) ischemia followed by reperfusion and ascorbic acid (IRA) and (v) in a sham group (S). We used morphometry to evaluate the amount of villous architecture, crypts, necrosis, hemorrhagic infarcts and inflammatory cells at the mesenteric and antimesenteric borders of the small intestine. RESULTS Ascorbic acid caused a significant reduction of antimesenteric villous hemorrhagic infarction (p<0.05) of the small intestine after ischemia followed by reperfusion as well as villous necrosis reduction at both borders after ischemia (p<0.05). The lesions found in the small intestine were more prominent along the antimesenteric margin. CONCLUSIONS Ascorbic acid pretreatment has a protective effect against the intestinal morphological lesions induced by ischemia-reperfusion injury in rats.

Angiogenesis as an indicator of metastatic potential in papillary thyroid carcinoma

UNLABELLED Angiogenesis is new blood vessel formation, a process that can lead to tumor development. Microvessel count has been correlated to metastasis in some neoplasias. PURPOSE To determine if measurement of microvessel density is useful in predicting metastasis to the cervical lymph node and prognosis in patients with papillary thyroid carcinoma. METHODS A retrospective analysis was performed in 30 patients that had undergone total thyroidectomy. They were divided in 2 groups of 15 patients--with and without metastatic disease. Immunohistochemistry was used to detect expression of CD34 in archival paraffin-embedded papillary thyroid tumors, and microvessel density was calculated based on it. Association between microvessel density and the presence of metastasis, according to histological subtype, disease recurrence, and AMES prognostic index groups was determined through statistical analysis. RESULTS The median microvessel density for the patient group without metastasis (200.0 microvessels/mm2) was apparently, but not significantly, less than that observed among metastatic disease patients (254.4 microvessels/mm2) (P=.20). When papillary carcinoma subtypes were analyzed, this difference became significant (P=02). The follicular variant exhibited a greater microvessel density than the other subtypes, independent of metastasis presence. There was an apparent, but not significant, tendency for a larger median microvessel density in the group of patients that presented recurrence (294.4 microvessels/mm2 vs 249.6 microvessels/mm2, P=.11). There was no relationship between risk level and microvessel density: in the low- and high-risk groups, the median MVD was 304.0 microvessels/mm2 and 229.6 microvessels/mm2, respectively (P=.27). CONCLUSIONS The results suggest that angiogenesis is more intense among metastatic tumors in the classic and the tall cell variants, indicating that microvessel count can be an indicator of the potential for metastasis in these subtypes of papillary thyroid carcinoma. Patients that developed recurrent disease had a tendency to exhibit higher angiogenesis; however, there was no association between microvessel density and the AMES prognostic index.

Accuracy of High Resolution CT in Assessing Idiopathic Pulmonary Fibrosis Histology by Objective Morphometric Index

To determine the accuracy of HRCT in assessing histology by objective morphometric index, twenty-five biopsy specimen-proved UIP were correlated with high-resolution CT (HRCT) by morphometric analysis. The scans were evaluated for the presence and extent of normal parenchyma, ground-glass attenuation, linear opacities, consolidation, honeycombing, vessels and bronchiectasis, and overall extent of histology involvement for normal parenchyma, honeycombing, alveolar septal inflammation, fibrosis, vessels, and bronchiectasis/bronchiolectasis. The comparison between morphometric measurements showed a strong correlation between HRCT and histologic parameters for extension (%) of normal tissue (p = 5 x 10(-5)), honeycombing (p = 6 x 10(-5)), and vessels (p = 0.0047). HRCT consolidation strongly correlated with alveolar septal inflammation (p = 0.015), whereas HRCT linear opacities had the highest correlation with histology for bronchiectasis or bronchiolectasis (p = 0.03). These associations also demonstrated that there was considerable residual scatter about the linear relationships found. By contrast, neither the ground glass patterns nor the bronchioectatic patterns determined by CT were associated with any histologic observation (p < 0.1). There was a borderline negative relationship between vessels determined by CT and histologic fibrosis (p = 0.069), i.e., the percentage of vessel patterns determined by CT was found to be lower when fibrosis was prominent histologically. Our results showed that HRCT patterns, usually employed to provide information about activity (ground glass) and fibrosis (consolidation) in IPF, failed to correlate with histology. On the other hand, chronic cystic lesions had a good correlation with histology. This finding suggests that in patients without a diffuse honeycomb pattern on HRCT, a lung biopsy may provide additional information. The more important limitation of our study was the lack of correlation related to the proximity of the biopsy site to the HRCT location evaluated by morphometry.

Bone marrow mononuclear cell therapy in experimental allergic asthma: Intratracheal versus intravenous administration

We hypothesized that the route of administration would impact the beneficial effects of bone marrow-derived mononuclear cell (BMDMC) therapy on the remodelling process of asthma. C57BL/6 mice were randomly assigned to two main groups. In the OVA group, mice were sensitized and challenged with ovalbumin, while the control group received saline using the same protocol. Twenty-four hours before the first challenge, control and OVA animals were further randomized into three subgroups to receive saline (SAL), BMDMCs intravenously (2×10(6)), or BMDMCs intratracheally (2×10(6)). The following changes were induced by BMDMC therapy in OVA mice regardless of administration route: reduction in resistive and viscoelastic pressures, static elastance, eosinophil infiltration, collagen fibre content in airways and lung parenchyma; and reduction in the levels of interleukin (IL)-4, IL-13, transforming growth factor-β and vascular endothelial growth factor. In conclusion, BMDMC modulated inflammatory and remodelling processes regardless of administration route in this experimental model of allergic asthma.

Nonhomogeneous Density of CD34 and VCAM-1 Alveolar Capillaries in Major Types of Idiopathic Interstitial Pneumonia

Integrin–immunoglobulin family ligand (CAMs) interactions between lung parenchymal cells (fibroblasts and epithelial cells) and integrin–extracellular matrix component interactions may be involved in the pathogenesis of idiopathic interstitial pneumonia (IIP). Among these, CD34 immunoquantitation allows determination of the degree of vascular proliferation (angiogenesis), whereas VCAM-1 immunoquantitation allows evaluation of the degree of endothelial activity and is strong evidence of inflammation. To validate the importance of vascular proliferation and endothelial cell activity within the alveolar walls and to explore the quantitative relationship between this factor and organizing fibrosis after parenchymal remodeling, we studied surgical lung biopsies in major IIP histologic patterns. We evaluated alveolar vascularity and activity in relation to the various degrees of organizing fibrosis in surgical lung biopsies of diffuse alveolar damage, nonspecific interstitial pneumonia, and usual interstitial pneumonia. Alveolar capillary endothelial cells were intensely immunoreactive with CD34 and VCAM-1. Vascular activity progressively increased in no-organizing fibrotic areas (normal, collapsed, and inflammatory septal areas), whereas vascular density gradually decreased as the degree of organizing fibrosis increased and was lower than that in control lungs in the most extensively fibrotic lesions (mural organizing fibrosis of usual interstitial pneumonia). These results indicate the presence of temporal nonhomogeneic vascular remodeling indiopathic interstitial pneumonia.

Systemic sclerosis and idiopathic interstitial pneumonia: histomorphometric differences in lung biopsies

OBJECTIVE: The aim of this study was to examine the parenchymal and extracellular matrix remodeling process in two histologic patterns-nonspecific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP)-in cases of idiopathic and sclerosis/systemic sclerosis (SSc)-associated interstitial pneumonia. METHODS: We examined 15 cases of idiopathic NSIP, 10 cases of idiopathic UIP, 5 cases of SSc-UIP and 9 cases of SSc-NSIP. In the lung parenchyma, epithelial cells, endothelial cells and myofibroblasts were evaluated by immunohistochemical staining, whereas histochemical staining was used in order to evaluate collagen/elastic fibers in the extracellular matrix. RESULTS: The percentage of surfactant protein A-positive epithelial cells was significantly greater in idiopathic NSIP than in SSc-NSIP, as well as being greater in idiopathic UIP than in SSc-UIP. Idiopathic NSIP and idiopathic UIP presented significantly higher immunoexpression of alpha smooth muscle actin in myofibroblasts than did SSc-NSIP and SSc-UIP. The percentage of CD34 endothelial cells in the pulmonary microvasculature was significant lower in idiopathic UIP than in SSc-UIP. The density of collagen fibers was significantly greater in idiopathic NSIP and idiopathic UIP than in SSc-NSIP and UIP. In contrast, the elastic fiber density was significantly lower in idiopathic UIP than in SSc-UIP. CONCLUSIONS: Increased collagen synthesis, destruction of elastic fibers, high myofibroblast proliferation and poor microvascularization might represent a remodeling process found in idiopathic interstitial pneumonia, whereas the reverse might represent a repair process in SSc-associated interstitial pneumonia.

Refractory remodeling of the microenvironment by abnormal type V collagen, apoptosis, and immune response in non-small cell lung cancer ☆

Collagen V shows promise as an inducer of the death response via caspases. Remodeling of the microenvironment by collagen V, tumoral/vascular apoptosis, and the immune response were evaluated, based on the prognosis of 65 patients with surgically excised non-small cell lung cancer. Immunofluorescence, immunohistochemistry, morphometry, tridimensional reconstruction, and a real-time polymerase chain reaction were used to evaluate the amount, structure, and molecular chains of collagen V, tumoral and vascular apoptosis, immune cells, and microvessel density. The impact of these markers was tested on follow-up until death from recurrent lung cancer occurred. A decreased and abnormal synthesis of collagen V was found to lead to increased angiogenesis due to a low endothelial death rate and a low immune response. A Cox model analysis, controlled for the lymph node stage, demonstrated that only collagen V and vascular apoptosis variables were significantly associated with survival time. A point at the median for collagen V and vascular apoptosis divided patients into 2 groups, each with a distinctive prognosis. Those with a collagen V higher than 9.40% and vascular apoptosis higher than 1.09% had a low risk of death (0.27 and 0.41, respectively) compared to those with a collagen V lower than 9.40% and vascular apoptosis lower than 1.09%. Collagen V and vascular apoptosis in resected non-small cell lung cancer was strongly related to the prognosis, suggesting that strategies aimed at preventing low collagen V synthesis, or local responses to low vascular apoptosis may have a greater impact in lung cancer treatment.

Síndromes hemorrágicas pulmonares

Pulmonary hemorrhage syndromes are characterized by bilateral pulmonary infiltrates, decreased serum levels of hemoglobin, and hypoxemia. The causes of pulmonary hemorrhage include: infections, vasculitis, coagulopathies and collagen diseases. The therapy consists of treating the underlying disease and providing ventilatory support. In some cases, performing plasmapheresis can be beneficial.