cord-factors and Pulmonary-Fibrosis

Trehalose dimycolate is a glycolipid component of the cell walls of mycobacteria, nocardia, and corynebacteria. When trehalose dimycolate is injected into certain strains of mice, they develop interstitial pneumonitis that is characterized by mononuclear cell infiltration of the alveolar walls, intra-alveolar hemorrhages, and in some animals, granuloma formation. The disorder is seldom fatal, and in approximately 4 weeks, the lungs are normal. There is strong evidence that T lymphocytes are essential for production of interstitial pneumonitis by trehalose dimycolate, but little is known about the mechanisms of lung injury in this model. The experiments described in this report were conducted to identify the roles of the various cells that accumulate in the lungs of mice with this form of interstitial pneumonitis. We found that Mac3+ macrophages were the first cells to appear in the alveolar walls. Increases in the number of L3T4+ T lymphocytes, Lyt2+ T lymphocytes, and surface-immunoglobulin-positive lymphocytes followed, but significant increases in the number of lymphoid cells were not observed until day 7, when the pulmonary lesions were well developed. Treatment of the mice with cyclophosphamide or anti-T-cell sera significantly reduced the number of lymphoid cells in the alveolar walls but did not affect the number of Mac3+ cells and did not affect development of intra-alveolar hemorrhages. Treatment with poly(I.C) significantly decreased the number of Mac3+ cells in the lungs, and these mice did not develop pulmonary hemorrhages. We conclude that although development of pulmonary lesions in trehalose dimycolate-treated mice is a T-cell-dependent process, macrophages are also essential and are more directly involved in production of the lung injury. We postulate that the lung lesions are the direct effect of macrophage-produced cytokines, such as tumor necrosis factor.

Topics: Animals; Cell Movement; Cord Factors; Cyclophosphamide; Female; G(M1) Ganglioside; Glycolipids; Glycosphingolipids; Immune Sera; Lymphocytes; Macrophages; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Phenotype; Poly I-C; Pulmonary Fibrosis

We showed previously that trehalose dimycolate (TDM) in oil administered intraperitoneally into susceptible mice produced interstitial and hemorrhagic pneumonitis by the seventh day after injection and that mature T cells are necessary for the production of these lesions. TDM has been reported to activate complement and to be chemotactic for macrophages in vitro. Accordingly, we looked for involvement of humoral mechanisms in the pathogenesis of TDM-induced pneumonitis. Genetically C5-deficient B10D2/oSn mice developed pulmonary lesions just as well as C5-sufficient mice. No activation of C3 occurred in the plasma of TDM-treated mice as determined by crossed immunoelectrophoresis. Some splitting of C3 occurred in bronchoalveolar lavage fluids, but this was similar in control and experimental mice. By immunofluorescence microscopy, there was no deposition of C3 or immunoglobulins (Ig) along the alveolar membranes. These findings and our published data provide additional evidence that TDM-induced interstitial inflammation in mice is exclusively a T-lymphocyte-dependent process.

Topics: Animals; Complement Activation; Complement C3; Complement C5; Cord Factors; Fluorescent Antibody Technique; Glycolipids; Immunoglobulins; Lung; Mice; Mice, Inbred Strains; Pulmonary Fibrosis

Trehalose dimycolate, a glycolipid component of the cell walls of mycobacteria, induces interstitial pneumonitis and alveolar hemorrhages in C57BL/6 and C57BL/10 mice. Homozygous nude (nu/nu) mice of these backgrounds are not susceptible to this form of pulmonary injury. However, after administration of T-lymphocyte-enriched spleen cell preparations from syngeneic donors, homozygous nude mice become susceptible to trehalose dimycolate. The observations suggest that production of pulmonary lesions by this mycobacterial component is dependent on T lymphocytes. While the mechanisms are still under study, we propose that trehalose dimycolate can function as an activator of T lymphocytes and that products of activated T cells are responsible for production of the pulmonary lesions.

Topics: Animals; Cord Factors; Female; Glycolipids; Hemorrhage; Immunity, Innate; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Nude; Pulmonary Alveoli; Pulmonary Fibrosis; Spleen; T-Lymphocytes

A single intraperitoneal injection of 10 micrograms of trehalose dimycolate (TDM) produced interstitial and hemorrhagic pneumonitis in C57BL/6 mice. As a part of an investigation of a possible role for cell-mediated immunity in the pathogenesis of this disorder, we found that reserpine, 3 mg/kg, given before, at the same time, or on Day 5 after administration of TDM, significantly reduced development of interstitial pneumonitis by Day 7. Smaller doses were less effective. Administration of reserpine, 3 or 2 mg/kg, 1 to 3 days after administration of TDM was lethal to most mice. Reserpine has been shown to inhibit expression of cell-mediated immune responses in mice, probably by causing intercellular release and degradation of vasoactive amines. Inhibition of pulmonary lesions by reserpine in TDM-treated mice suggests that a similar mechanism may be involved in the pathogenesis of TDM-induced lung injury.

Topics: Animals; Cord Factors; Dose-Response Relationship, Drug; Glycolipids; Immunity, Cellular; Mice; Mice, Inbred C57BL; Pulmonary Fibrosis; Reserpine