Faculty Bibliography

Silicosis is characterized by fibrosing nodular lesions that may eventually develop into progressive massive fibrosis (PMF). Cytokines (interleukin-1beta [IL-1beta], tumor necrosis factor-alpha [TNF-alpha] and growth factors insulin-like growth factor-1 [IGF-1] platelet-derived growth factor [PDGF]) have been implicated in the formation of these lesions. TGF-beta promotes extracellular matrix accumulation by upregulating collagen and fibronectin gene expression, and inhibits matrix degradation by decreasing secretion of proteases and increasing secretion of protease inhibitors. We hypothesized that TGF-beta is associated with matrix deposition and fibrosis in silicosis. To test this hypothesis we studied early and late nodular lesions and PMF (11 cases and two controls) with immunohistochemistry, using rabbit polyclonal antibody to the purified whole molecule of TGF-beta in Bouin's fixed lung tissue. This antibody is reactive with both intra- and extracellular forms of TGF-beta. In the control lungs, small amounts of TGF-beta were present in the bronchial epithelium, macrophages, bronchial and vascular smooth muscle, and bronchial glands. There was minimal to moderate staining in the early silicotic peribronchiolar lesions. In the nodular lesions of silicosis, central hyalinized areas contained the maximum staining for TGF-beta. Fibroblasts in the periphery of the nodular lesions were also positive. In acute silicosis, there was marked staining of hyperplastic alveolar epithelium. Macrophages were markedly positive. In the PMF lesions, large areas of scar tissue contained TGF-beta. These data suggest a major role for TGF-beta in silicosis, particularly in the formation of silicotic nodules and the development of PMF

SETTING: Bellevue Hospital, a large public hospital in New York City. OBJECTIVE: To discern the clinical characteristics of spinal tuberculosis (Pott's disease) in patients with the human immunodeficiency virus (HIV). DESIGN: Review of all cases of spinal tuberculosis seen at the hospital from 1988 to 1995, with comparison of HIV-positive and HIV-negative cases. Chart reviews for all cases were performed and information regarding signs and symptoms, neurological findings, laboratory and radiographic data, medical and surgical treatment and eventual outcome were recorded. RESULTS: We collected 26 cases of tuberculosis of the spine between July 1988 and June 1995. Seven of our 26 patients (27%) were HIV seropositive. Six of these were PPD+ on presentation. When compared with HIV-negative patients, those with HIV and spinal tuberculosis had similar clinical presentations; most patients had a diagnosis made with percutaneous needle aspiration biopsy of clinically involved areas, and open procedures added little diagnostic information. Most were treated without surgery, and response to antituberculosis therapy was uniformly good. CONCLUSION: We conclude that clinical presentations of spinal tuberculosis are similar in HIV-positive and -negative patients, and good outcomes can be expected with regard to mycobacterial disease

Asbestosis is a fibrotic and inflammatory interstitial lung disease occurring after chronic occupational exposure to asbestos. An alveolitis has been described with activated alveolar macrophages and increased neutrophils as sampled by bronchoalveolar lavage (BAL). Animal models and in vitro studies demonstrate that asbestos can stimulate alveolar macrophages to release neutrophil chemotactic factor. We performed BAL on 18 nonsmoking individuals with asbestos exposure and observed a twofold increase in percent neutrophils recovered. Alveolar macrophages cultured in vitro from the asbestos-exposed individuals spontaneously released significant amounts of the neutrophil chemotaxin, interleukin-8 (IL-8). In addition, the alveolar macrophages expressed a 2.7-fold increase in steady state mRNA levels compared to unexposed normal controls utilizing the reverse transcriptase/polymerase chain reaction. In vitro experiments confirmed that crocidolite or chrysotile asbestos could stimulate the release of IL-8 from mononuclear phagocytes in a dose-dependent fashion. We conclude that asbestos exposure causes a mild neutrophilic alveolitis, and that IL-8 is one potential mediator capable of contributing to this inflammation in the lower respiratory tract

We analyzed the clinical and laboratory findings and outcome of 173 patients hospitalized at our institution from 1983 to 1994 with multidrug-resistant tuberculosis (MDR-TB) and evaluated outcome. The 173 patients (mean age 40 +/- 1 yr) were predominantly male (92%), African American or Hispanic (80%), and mostly undomiciled. Over half (52%) were known to be HIV-infected. HIV-positive MDR-TB patients had significantly more pulmonary and constitutional symptoms, more extrapulmonary disease, and fewer cavitary lesions on chest radiographs. Fifty-five percent of the patients in the cohort have died; mortality was significantly greater for HIV-positive than HIV-negative (72% versus 20%, p < 0.01). The median duration of survival of MDR-TB patients was 22 +/- 1 mo. Overall, extrapulmonary involvement was a risk factor for shorter survival, while a cavitary lesion on initial chest film and institution of appropriate treatment were positive predictors of survival. In HIV+ patients, only appropriate therapy was associated with prolonged survival (median of 14.1 mo). Interestingly, there was a trend toward better outcome in the first half of the decade reviewed. We conclude that although mortality from MDR-TB is high in both HIV-positive and HIV-negative patients, institution of appropriate therapy is the factor most strongly associated with a favorable outcome. Development of new diagnostic and therapeutic strategies for MDR-TB are urgently needed

Leishmania are parasites that survive within macrophages by mechanism(s) not entirely known. Depression of cellular immunity and diminished production of interleukin 1 beta (IL-1 beta) and tumor necrosis factor alpha are potential ways by which the parasite survives within macrophages. We examined the mechanism(s) by which lipophosphoglycan (LPG), a major glycolipid of Leishmania, perturbs cytokine gene expression. LPG treatment of THP-1 monocytes suppressed endotoxin induction of IL-1 beta steady-state mRNA by greater than 90%, while having no effect on the expression of a control gene. The addition of LPG 2 h before or 2 h after endotoxin challenge significantly suppressed steady-state IL-1 beta mRNA by 90% and 70%, respectively. LPG also inhibited tumor necrosis factor alpha and Staphylococcus induction of IL-1 beta gene expression. The inhibitory effect of LPG is agonist-specific because LPG did not suppress the induction of IL-1 beta mRNA by phorbol 12-myristate 13-acetate. A unique DNA sequence located within the -310 to -57 nucleotide region of the IL-1 beta promoter was found to mediate LPG's inhibitory activity. The requirement for the -310 to -57 promoter gene sequence for LPG's effect is demonstrated by the abrogation of LPG's inhibitory activity by truncation or deletion of the -310 to -57 promoter gene sequence. Furthermore, the minimal IL-1 beta promoter (positions -310 to +15) mediated LPG's inhibitory activity with dose and kinetic profiles that were similar to LPG's suppression of steady-state IL-1 beta mRNA. These findings delineated a promoter gene sequence that responds to LPG to act as a 'gene silencer', a function, to our knowledge, not previously described. LPG's inhibitory activity for several mediators of inflammation and the persistence of significant inhibitory activity 2 h after endotoxin challenge suggest that LPG has therapeutic potential and may be exploited for therapy of sepsis, acute respiratory distress syndrome, and autoimmune diseases