Differential systemic and intrapulmonary TNF-alpha production in Candida sepsis during immunosuppression

Abstract

Candida albicans (CA) increasingly causes septic shock, acute lung injury, and multiple organ damage during immunosuppression-related neutropenia. However, the effects of neutrophil (PMN) depletion on induction of tumor necrosis factor-alpha (TNF) by CA and its potential mediation of Candida septic shock are unknown. We hypothesized that reduced CA uptake by circulating PMNs during cyclophosphamide (CY)-related neutropenia sensitizes to TNF-mediated shock from enhanced cytokine production after phagocytosis by tissue macrophages. Absolute or relative neutropenia (PMNs < or = 500/microliters or 2,500/microliters) was modeled in rats by intraperitoneal CY 4-8 days before 10(9) yeast-phase CA (acute studies < or = 24 h, n = 81 animals) or 10(6) CA (subacute studies < or = 72 h, n = 25). Compared with neutrophil-sufficient rats, absolute neutropenia accelerated hemodynamic collapse and respiratory distress after 10(9) CA, and pulmonary microvascular permeability was amplified. These changes evolved without increased candidemia or elevations in bioactive or antigenic serum TNF, which remained low even at death (42.3 +/- 14.8 U/ml vs. 12.6 +/- 2.9 U/ml for CY + saline, means +/- SE, P = NS). In contrast, significant TNF in lung tissue and bronchoalveolar lavage fluid (BALF) was evident within 6 h in CY + 10(9) CA rats. Electron microscopy confirmed hyphal proliferation into alveoli from yeast within mononuclear cells in lung capillaries. Subacute disseminated candidiasis after 10(6) CA was not associated with elevated serum, lung, or BALF TNF. We conclude that differential systemic and intrapulmonary TNF production occur in CA septic shock during preexisting neutropenia, with compartmentalized TNF production in the lower respiratory tract accompanying yeast-mycelial transformation. Thus TNF is not an obligate mediator of acute candidemic shock or subacute disseminated candidiasis during CY-induced immunosuppression but may initiate pulmonary injury accompanying high-grade candidemia.

Direct Binding of Toll-Like Receptor 2 to Zymosan, and Zymosan-Induced NF-κB Activation and TNF-α Secretion Are Down-Regulated by Lung Collectin Surfactant Protein A

“…Although the study did not elucidate the mechanism of SP-A's impact, it is possible to assume that the binding of SP-A to TLR may alter the interaction of Candida to the cell surface receptor, resulting in the down-regulation of proinflammatory cytokine release. Intrapulmonary TNF-␣ production causes local inflammatory tissue injury and lethal septic shock in Candida sepsis during immunosuppression (11). Taken together with this study, these works give credence to the important physiological role of SP-A in regulating pulmonary inflammation elicited by fungi.…”

“…Intratracheal challenge of zymosan has been shown to induce pulmonary inflammation in animal models (10). Intrapulmonary TNF-␣ production causes lung tissue injury and severe pulmonary inflammation in disseminated candidemia under immunosuppressive conditions (11).…”

Role of Alveolar Macrophages in Candida -Induced Acute Lung Injury

“…However, the behavior of AMs during disseminated candidiasis is insufficiently elucidated. Lechner et al (15) reported that tumor necrosis factor (TNF) levels in BALF of neutropenic animals with candidemia are elevated, whereas TNF levels in serum remain low, even at death. They assumed that impaired clearance of yeast-phase C. albicans by circulating polymorphonuclear cells leads to extensive yeast mycelium transformation in the pulmonary vasculature, hyphal outgrowth from pulmonary capillaries, and increased TNF production by AMs in response to hyphal elements in the distal air spaces.…”

Glibenclamide‐induced inhibition of the expression of inducible nitric oxide synthase in cultured macrophages and in the anaesthetized rat

“…Another blood sample (0.6 ml) for the measurement of plasma TNFcx levels was obtained at 90 min after the injection of LPS, a time point at which the rise in TNFoE after LPS is maximal (Lechner et al, 1993). The amounts of TNFaE in the plasma were measured by an enzyme linked immunoadsorbent assay (ELISA) as previously described (Lechner et al, 1992). …”