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Antifungal Treatments Delineate a Correlation between Cathepsins and Cytokines in Murine Model of Invasive Aspergillosis.

Mittal A, Gahlaut A, Sharma GL, Dabur R - Indian J Pharm Sci (2013)

Bottom Line: In the present murine model of invasive pulmonary aspergillosis, on seventh day of Aspergillus fumigatus infection, both kidney and liver showed significant (P<0.05) fungal burdens, which was also confirmed by histological analyses.The data illustrate that the reduction in fungal load in both organs probably results in a decreased local inflammatory response, as measured by decreased levels of interleukin-4 and interleukin-10 and increased level of interferon gamma in the antifungal compounds treated mice.Interestingly, this altered level of cytokines relates well with the activity level of cathepsins, that is decreased in interleukines (interleukinL-4/interleukin-10) and cathepsins (cathepsin B, cathepsin C and cathepsin L); and increase in interferon gamma and cathepsin H levels in the mice treated with antifungal compounds were observed.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University College, Kurukshetra University, Kurukshetra-136 119, India.

ABSTRACT
In the pathogenesis of invasive pulmonary aspergillosis both fungal and host factors play roles. Though cytokines and phagocyte, as host factors, have been shown to participate in defence against Aspergillus species yet the role of cysteine proteases, that is cathepsins, a lysosomal enzymes of phagocytes, remains unknown in fungal infection. Studies are available which shows that cytokines regulate the cysteine proteases processed immune molecules for their further action but their relationship with each other under fungal infection is not clear. Therefore, in this study, we demonstrate the substantial role of cathepsins and cytokines in aspergillosis. In the present murine model of invasive pulmonary aspergillosis, on seventh day of Aspergillus fumigatus infection, both kidney and liver showed significant (P<0.05) fungal burdens, which was also confirmed by histological analyses. The activity profiles of four cathepsins in the kidney and liver tissue were analysed and correlated with blood cytokines level in the presence and absence of antifungal compounds (amphotericin B, a standard drug and 2-(3,4-dimethyl-2,5-dihydro-1H-pyrrole-2-yl)-1-methylethyl pentanoate, isolated in our laboratory from natural source) treatment. The data illustrate that the reduction in fungal load in both organs probably results in a decreased local inflammatory response, as measured by decreased levels of interleukin-4 and interleukin-10 and increased level of interferon gamma in the antifungal compounds treated mice. Interestingly, this altered level of cytokines relates well with the activity level of cathepsins, that is decreased in interleukines (interleukinL-4/interleukin-10) and cathepsins (cathepsin B, cathepsin C and cathepsin L); and increase in interferon gamma and cathepsin H levels in the mice treated with antifungal compounds were observed. These observations support not only the negative (cathepsin B, cathepsin C and cathepsin L) and positive (cathepsin H) role of cathepsins in aspergillosis but also prove the role of cytokines in remodelling of immune response. Overall, the study reveals a correlation between cathepsins and cytokines and their regulatory role in fungal mediated infection.

No MeSH data available.


Related in: MedlinePlus

Histopathology of mice organs.Representative photomicrographs of H and E-stained (original magnification ×100) tissue sections from control, infected, and treated mice groups on 7 day after infection. (a) H and E-stained sections of kidney tissue; diverse histological changes were observed in tissues of kidney such as kidney cell necrosis with inflammatory cells infiltration (indicated with yellow dotted arrow) (b) H and E-stained sections of liver tissue. Yellow dotted arrow indicates appearance of inflammatory molecules. But there are huge recovery from necrosis and also decrease in number of inflammatory molecules (blue dotted colour) in both liver and kidney tissues after antifungal compound treatment.
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Figure 3: Histopathology of mice organs.Representative photomicrographs of H and E-stained (original magnification ×100) tissue sections from control, infected, and treated mice groups on 7 day after infection. (a) H and E-stained sections of kidney tissue; diverse histological changes were observed in tissues of kidney such as kidney cell necrosis with inflammatory cells infiltration (indicated with yellow dotted arrow) (b) H and E-stained sections of liver tissue. Yellow dotted arrow indicates appearance of inflammatory molecules. But there are huge recovery from necrosis and also decrease in number of inflammatory molecules (blue dotted colour) in both liver and kidney tissues after antifungal compound treatment.

Mentions: To answer another question, that is the fungal burden propagation in the initial (lungs) and deeper organs (liver and kidney) of the infected mice, CFU was measured only on the seventh day in A. fumigatus infected mice and data compared with antifungal compound treated mice. As shown in fig. 2, data explains not only the significant fungal burden propagation in the deeper organs of the infected mice but also depicts the strong protective effect of DHP on aspergillosis. This fact was further evaluated using histological approach. Fig. 3a and b, shows the large number of inflammatory molecules in both organs (kidney and liver) due to fungal infection. Necrosis was also observed in fungal infected kidney cells. But the level of these inflammatory molecules and cell necrosis gets decreased after DHP treatment. It is very clear that cathepsins has some role in fungal infection and infection propagates well in the deeper organs and IPA converts into systemic aspergillosis with time. In other words, our model is ready for further investigations.


Antifungal Treatments Delineate a Correlation between Cathepsins and Cytokines in Murine Model of Invasive Aspergillosis.

Mittal A, Gahlaut A, Sharma GL, Dabur R - Indian J Pharm Sci (2013)

Histopathology of mice organs.Representative photomicrographs of H and E-stained (original magnification ×100) tissue sections from control, infected, and treated mice groups on 7 day after infection. (a) H and E-stained sections of kidney tissue; diverse histological changes were observed in tissues of kidney such as kidney cell necrosis with inflammatory cells infiltration (indicated with yellow dotted arrow) (b) H and E-stained sections of liver tissue. Yellow dotted arrow indicates appearance of inflammatory molecules. But there are huge recovery from necrosis and also decrease in number of inflammatory molecules (blue dotted colour) in both liver and kidney tissues after antifungal compound treatment.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3928733&req=5

Figure 3: Histopathology of mice organs.Representative photomicrographs of H and E-stained (original magnification ×100) tissue sections from control, infected, and treated mice groups on 7 day after infection. (a) H and E-stained sections of kidney tissue; diverse histological changes were observed in tissues of kidney such as kidney cell necrosis with inflammatory cells infiltration (indicated with yellow dotted arrow) (b) H and E-stained sections of liver tissue. Yellow dotted arrow indicates appearance of inflammatory molecules. But there are huge recovery from necrosis and also decrease in number of inflammatory molecules (blue dotted colour) in both liver and kidney tissues after antifungal compound treatment.
Mentions: To answer another question, that is the fungal burden propagation in the initial (lungs) and deeper organs (liver and kidney) of the infected mice, CFU was measured only on the seventh day in A. fumigatus infected mice and data compared with antifungal compound treated mice. As shown in fig. 2, data explains not only the significant fungal burden propagation in the deeper organs of the infected mice but also depicts the strong protective effect of DHP on aspergillosis. This fact was further evaluated using histological approach. Fig. 3a and b, shows the large number of inflammatory molecules in both organs (kidney and liver) due to fungal infection. Necrosis was also observed in fungal infected kidney cells. But the level of these inflammatory molecules and cell necrosis gets decreased after DHP treatment. It is very clear that cathepsins has some role in fungal infection and infection propagates well in the deeper organs and IPA converts into systemic aspergillosis with time. In other words, our model is ready for further investigations.

Bottom Line: In the present murine model of invasive pulmonary aspergillosis, on seventh day of Aspergillus fumigatus infection, both kidney and liver showed significant (P<0.05) fungal burdens, which was also confirmed by histological analyses.The data illustrate that the reduction in fungal load in both organs probably results in a decreased local inflammatory response, as measured by decreased levels of interleukin-4 and interleukin-10 and increased level of interferon gamma in the antifungal compounds treated mice.Interestingly, this altered level of cytokines relates well with the activity level of cathepsins, that is decreased in interleukines (interleukinL-4/interleukin-10) and cathepsins (cathepsin B, cathepsin C and cathepsin L); and increase in interferon gamma and cathepsin H levels in the mice treated with antifungal compounds were observed.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University College, Kurukshetra University, Kurukshetra-136 119, India.

ABSTRACT
In the pathogenesis of invasive pulmonary aspergillosis both fungal and host factors play roles. Though cytokines and phagocyte, as host factors, have been shown to participate in defence against Aspergillus species yet the role of cysteine proteases, that is cathepsins, a lysosomal enzymes of phagocytes, remains unknown in fungal infection. Studies are available which shows that cytokines regulate the cysteine proteases processed immune molecules for their further action but their relationship with each other under fungal infection is not clear. Therefore, in this study, we demonstrate the substantial role of cathepsins and cytokines in aspergillosis. In the present murine model of invasive pulmonary aspergillosis, on seventh day of Aspergillus fumigatus infection, both kidney and liver showed significant (P<0.05) fungal burdens, which was also confirmed by histological analyses. The activity profiles of four cathepsins in the kidney and liver tissue were analysed and correlated with blood cytokines level in the presence and absence of antifungal compounds (amphotericin B, a standard drug and 2-(3,4-dimethyl-2,5-dihydro-1H-pyrrole-2-yl)-1-methylethyl pentanoate, isolated in our laboratory from natural source) treatment. The data illustrate that the reduction in fungal load in both organs probably results in a decreased local inflammatory response, as measured by decreased levels of interleukin-4 and interleukin-10 and increased level of interferon gamma in the antifungal compounds treated mice. Interestingly, this altered level of cytokines relates well with the activity level of cathepsins, that is decreased in interleukines (interleukinL-4/interleukin-10) and cathepsins (cathepsin B, cathepsin C and cathepsin L); and increase in interferon gamma and cathepsin H levels in the mice treated with antifungal compounds were observed. These observations support not only the negative (cathepsin B, cathepsin C and cathepsin L) and positive (cathepsin H) role of cathepsins in aspergillosis but also prove the role of cytokines in remodelling of immune response. Overall, the study reveals a correlation between cathepsins and cytokines and their regulatory role in fungal mediated infection.

No MeSH data available.


Related in: MedlinePlus