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The response of hepatic acute phase proteins during experimental pulmonary tuberculosis
R Hernández-Pando1, A K Arriaga, C A Panduro
1Department of Pathology, Instituto Nacional de la Nutrición Salvador Zubiran, México City, México.
Abstract:
A mouse model of pulmonary tuberculosis induced by the intratracheal instillation of live and virulent mycobacteria strain H37-Rv was used to study the relationship of the histopathological changes with the kinetics of local production and circulating levels of interleukin 6 (IL-6) and the gene expression of acute phase proteins (APP) in the liver. The histopathological studies showed a mononuclear inflammatory infiltrate located in the perivascular, peribronchial, and interstitial areas, with granulomas which started to form 2 weeks after the infection. Numerous IL-6 immunostained activated macrophages were observed in the inflammatory infiltrate, particularly in the interstitial-intralveolar compartment and granulomas, coexisting with a high IL-6 mRNA concentration determined by reverse transcription polimerase chain reaction in lung homogenates, particularly at day 21 of infection. Two peaks of IL-6 demonstrated by ELISA in lung homogenates and sera were observed at day 3 and 21 of infection, being higher on the latter. The hepatic APP mRNA transcription (alpha1-acid glycoprotein, fibrinogen, complement factor 4) analyzed by Northern blot showed a rapid and high increase at day one postinfection, which rapidly decreased and showed another second peak at day 21, when granulomas reached full maturity and the maximal production of IL-6 was observed. At the same time the liver mRNA concentrations of the negative APP albumin showed a substantial decrease. From 1 to 4 months after M. tuberculosis intratracheal instillation, histopathological changes of more severity (pneumonia, necrosis) and chronicity (interstitial fibrosis) were seen, as well as small groups of IL-6 immunostained macrophages in the pneumonic areas, granulomas and perivascular compartments, in coexistence with low IL-6 expression. During this advanced stage of the disease a high mRNA concentration of alpha1-acid glycoprotein and fibrinogen associated with low expression of the albumin gene in the liver continued. Thus, it seems that the time course of hepatic APP genetic expression in experimental pulmonary tuberculosis is related to the production of IL-6 and relevant histopathological changes, particularly the formation of granuloma.
Insights
This study links inflammation in mouse lungs with interleukin-6 (IL-6) production and acute phase protein (APP) gene expression. It reveals a correlation between IL-6 levels, APP gene expression, and the severity of tuberculosis-induced lung pathology.
Area of Science:
- Immunology
- Pathology
- Molecular Biology
Background:
- Tuberculosis (TB) is a significant global health challenge.
- Understanding the host's immune response, including cytokine and acute phase protein dynamics, is crucial for TB pathogenesis.
- Interleukin-6 (IL-6) and acute phase proteins (APPs) are key inflammatory mediators.
Purpose of the Study:
- To investigate the relationship between histopathological changes in pulmonary tuberculosis and the kinetics of IL-6 production.
- To examine the correlation between IL-6 levels and the gene expression of APPs in the liver during experimental TB.
- To elucidate the temporal dynamics of these markers in relation to disease progression.
Main Methods:
- Establishment of a mouse model of pulmonary tuberculosis via intratracheal instillation of Mycobacterium tuberculosis H37-Rv.
- Histopathological analysis of lung tissues to assess inflammatory infiltrate and granuloma formation.
- Quantification of IL-6 levels (mRNA and protein) in lung homogenates and sera using RT-PCR and ELISA.
- Analysis of hepatic APP gene expression (alpha1-acid glycoprotein, fibrinogen, complement factor 4, albumin) using Northern blot.
Main Results:
- Histopathological findings revealed mononuclear infiltrates and granuloma formation starting at 2 weeks post-infection.
- IL-6 was significantly upregulated in lung tissues, particularly in activated macrophages within inflammatory sites and granulomas, peaking at day 21.
- Two peaks of IL-6 were observed in lung homogenates and sera (days 3 and 21), with higher levels at day 21.
- Hepatic APP mRNA (alpha1-acid glycoprotein, fibrinogen, complement factor 4) showed a rapid increase at day 1, with a second peak at day 21, coinciding with mature granulomas and peak IL-6.
- Albumin mRNA levels, a negative APP, decreased significantly during infection.
- Advanced stages (1-4 months) showed persistent pneumonia, necrosis, fibrosis, and continued high APP expression despite lower IL-6 levels.
Conclusions:
- The temporal profile of hepatic APP gene expression in experimental pulmonary tuberculosis is closely linked to IL-6 production.
- These molecular events correlate with the observed histopathological changes, especially granuloma maturation and disease severity.
- IL-6 and APP dynamics serve as important indicators of host response and disease progression in TB.