Publications

Mycobacterium tuberculosis overcomes macrophage bactericidal activities and persists intracellularly. One mechanism by which M. tuberculosis avoids macrophage killing might be through inhibition of IFN-gamma-mediated signaling. In this study we provide evidence that at least two distinct components of M. tuberculosis, the 19-kDa lipoprotein and cell wall peptidoglycan (contained in the mycolylarabinogalactan peptidoglycan (mAGP) complex), inhibit macrophage responses to IFN-gamma at a transcriptional level. Moreover, these components engage distinct proximal signaling pathways to inhibit responses to IFN-gamma: the 19-kDa lipoprotein inhibits IFN-gamma signaling in a Toll-like receptor (TLR)2-dependent and myeloid differentiation factor 88-dependent fashion whereas mAGP inhibits independently of TLR2, TLR4, and myeloid differentiation factor 88. In addition to inhibiting the induction of specific IFN-gamma responsive genes, the 19-kDa lipoprotein and mAGP inhibit the ability of IFN-gamma to activate murine macrophages to kill virulent M. tuberculosis without inhibiting production of NO. These results imply that inhibition of macrophage responses to IFN-gamma may contribute to the inability of an apparently effective immune response to eradicate M. tuberculosis.

Acetylation of histones leads to conformational changes of DNA. We have previously shown that the histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), induced cell cycle arrest, differentiation, and apoptosis. In addition to their antitumor effects as single agents, HDAC inhibitors may cause conformational changes in the chromatin, rendering the DNA more vulnerable to DNA damaging agents. We examined the effects of SAHA on cell death induced by topo II inhibitors in breast cancer cell lines. Topo II inhibitors stabilize the topo II-DNA complex, resulting in DNA damage. Treatment of cells with SAHA promoted chromatin decondensation associated with increased nuclear concentration and DNA binding of the topo II inhibitor and subsequent potentiation of DNA damage. While SAHA-induced histone hyperacetylation occurred as early as 4 h, chromatin decondensation was most profound at 48 h. SAHA-induced potentiation of topo II inhibitors was sequence-specific. Pre-exposure of cells to SAHA for 48 h was synergistic, whereas shorter pre-exposure periods abrogated synergy and exposure of cells to SAHA after the topo II inhibitor resulted in antagonistic effects. Synergy was not observed in cells with depleted topo II levels. These effects were not limited to specific types of topo II inhibitors. We propose that SAHA significantly potentiates the DNA damage induced by topo II inhibitors; however, synergy is dependent on the sequence of drug administration and the expression of the target. These findings may impact the clinical development of combining HDAC inhibitors with DNA damaging agents.

PURPOSE

To determine the effect of pulmonary fibrosis on survival in an unselected group of patients with hypersensitivity pneumonitis.

METHODS

We identified 72 patients with hypersensitivity pneumonitis confirmed by surgical lung biopsy in the database of the Clinical Interstitial Lung Disease Program at the National Jewish Medical and Research Center. All biopsy specimens were scored according to the presence or absence of fibrosis. Comparisons were made between patients with (fibrotic group) and without (nonfibrotic group) pathologic fibrosis. Vital status was ascertained and Kaplan-Meier curves were plotted. Cox regression analysis was used to determine predictors of survival.

RESULTS

Forty-six patients were classified as fibrotic and 26 as nonfibrotic. Twenty-nine percent had exposure to a bird antigen, 33% had exposure to a microbial antigen, and 38% had unknown exposure. Patients with fibrosis were significantly older, showed greater restrictive lung physiology, and had greater all-cause and respiratory mortality. Median survival in fibrotic patients was 7.1 years, which was significantly less than survival in those without fibrosis. In an age-adjusted regression analysis, antigen class, symptom duration, and lung function had no effect on survival. Only the presence of pathologic fibrosis was predictive of increased mortality (hazard ratio = 6.01; 95% confidence interval: 1.68 to 21.45; P = 0.006).

CONCLUSION

Pulmonary fibrosis is associated with diminished survival in patients with hypersensitivity pneumonitis.

While active against Herpesviridae, oral aciclovir is limited by low and inconsistent bioavailability. Modification of aciclovir by valine esterification, producing valaciclovir, results in significant increases in systemic aciclovir plasma levels. The exact mechanism of increased absorption with valaciclovir is not fully determined but probably involves intestinal dipeptide transporters, followed by rapid ester hydrolysis in the small intestine and liver. The enhanced pharmacokinetics of valaciclovir have translated into improvements in clinical efficacy and patient convenience.