THE PATHOGENESIS OF MALARIA ACUTE RESPIRATORY DISTRESS SYNDROME (MA-ARDS): MODIFICATION OF THE LIPID PROFILE, ANTIOXIDANT DEFENCES AND CYTOKINE CONTENT IN DIFFERENT TISSUES OF MALARIA INFECTED MICE
Tesi di Dottorato
Data di Pubblicazione:
2014
Citazione:
THE PATHOGENESIS OF MALARIA ACUTE RESPIRATORY DISTRESS SYNDROME (MA-ARDS): MODIFICATION OF THE LIPID PROFILE, ANTIOXIDANT DEFENCES AND CYTOKINE CONTENT IN DIFFERENT TISSUES OF MALARIA INFECTED MICE / D. Scaccabarozzi ; tutor: D. Taramelli ; correlatore: M.F. Omodeo Salè ; coordinatore: M. Clerici. DIPARTIMENTO DI SCIENZE FARMACOLOGICHE E BIOMOLECOLARI, 2014 Feb 03. 26. ciclo, Anno Accademico 2013. [10.13130/scaccabarozzi-diletta_phd2014-02-03].
Abstract:
INTRODUCTION Malaria is a major health problem, with more than 650.000 deaths and 200 million clinical cases each year. Respiratory distress as malaria associated acute respiratory distress syndrome (MA-ARDS) is a common complication. The pathogenesis of MA-ARDS is mainly inflammatory and one of the main observation is the presence of abundant monocytes and macrophages inside the blood capillaries, in the interstitium and also in alveolar spaces. Malaria pigment or haemozoin (Hz) is often seen in these cells reflecting active phagocytosis and leads to the production of cytokines and other inflammatory mediators. Multiple organ dysfunctions are described in MA-ARDS, including liver damages. ARDS in non malarious patients is often associated with disorders of the lung surfactant, which can lead to the increase in surface tension, alveolar collapse and loss of the liquid balance in the lungs. Surfactant is known to reduce the surface tension at the air–liquid interface of lung epithelia and to regulate the local host immune response. It can be separated into a surface active Large Aggregate fractions (LA), representing a reservoir for the surface film located at the air-liquid interface of the alveoli and a less surface active, Small Aggregate fraction (SA). It is not known at present if alterations of the surfactant also exist in MA-ARDS and how they may contribute to the pathology and the development of the inflammatory response.
AIM The aim of our studies was to perform a comprehensive analysis of the local and systemic inflammatory response present in MA-ARDS and to analyse the lipid profile of the pulmonary surfactant, the lung and liver tissues and plasma using two different models of murine malaria of similar gravity, but different involvement of lungs or liver. In particular, we studied C57BL/6J mice infected with two different species of Plasmodium: Plasmodium berghei NK65 strain which induces MA-ARDS and Plasmodium chabaudi (PcAS), which does not. The two models allowed us to directly compare the different pathological manifestation of the same infection in order to identify peculiarities which could be exploited for novel therapeutic interventions.
RESULTS AND DISCUSSION
Macroscopic and functional analysis of lung tissues in the two strains. The lungs of PbNK65 infected mice were swollen, increased in weight and with a dark brown aspect due to micro haemorrhages and to the deposition of Hz clusters in concentrations significantly higher compared to the lungs of mice infected with PcAS. The expression of TNF-α and IFN- was increased only in PbNK65 mice, indicating that these cytokines are induced specifically during MA-ARDS and are not a consequence of malaria infection. This hypothesis was confirmed by the decrease of lung weight and of the CD8+ cells infiltrate, and the reduction /delay in mortality rates seen in PbNK65 mice treated with DEX without a concomitant reduction in parasitaemia. Therefore, DEX seems to ameliorate MA-ARDS, not by inhibiting parasite growth but rather by modulating the immunopathology and the inflammatory response. A significant increase of the total phospholipid (PL) content and cholesterol esters (ChoE) was observed in PbNK65 lungs and was reverted by DEX. Moreover, compared to the control mice (CTR), the fatty acid distribution of lung ChoE was characterized by higher levels of the polyunsaturated fatty acid and an high linoleic/oleic ratio typical of plasma ChoE. All these features confirm a strict correlation between the interstitial oedema and the infiltration of plasma lipoproteins during MA-ARDS. Protein and lipid composition of surfactant and plasma of infected mice. The total bronchoalveolar lavage (BAL) of PbNK65 mice showed a significant increase in the protein levels compare
Tipologia IRIS:
Tesi di dottorato
Keywords:
Malaria ; ARDS ; mice ; lipids ; cytokines
Elenco autori:
D. Scaccabarozzi
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