Acute lung injury during bacterial or fungal sepsis

Abstract

We compared physiological and ultrastructural indices of acute lung injury (ALI) during septic shock caused by taxonomically diverse pathogens to distinguish ALI due to endogenous inflammatory mediators vs. microbial exotoxins or other factors. Conscious rats were infected i.v. with gram-negative Escherichia coli (EC, serotype 055:B5), exotoxin-C producing gram-positive Staphylococcus aureus (SA), or yeast-phase Candida albicans (CA, a clinical isolate). Viable inocula of 10(10) EC, 10(10) SA, or 10(9) CA caused lethal shock in < 24 h, but distinct types of ALI were noted after bacteria vs. fungi. Within 0.5 h of EC infection, leukocytes marginated in the lung vasculature; by death at 6-14 h, animals were hyperoxemic but not acidemic, and showed slight interstitial edema with increased wet/dry weight ratios (W/D = 5.22 +/- 0.10, mean +/- SE, vs. 4.86 +/- 0.07 in controls, P < 0.05). Similarly mild ALI occurred after 10(10) SA. In contrast, within 0.5 h of CA infection, yeast were visible within lung intravascular leukocytes. By death at 6-12 h, CA animals showed hyperoxic acidemia and moderate ALI with capillary obstruction, interstitial hemorrhage, and elevated lung W/D (5.52 +/- 0.13, P < 0.01 vs. controls) associated with yeast-mycelial transformation. Prior neutropenia accelerated mortality and worsened ALI after CA, with hypoxemic acidemia, increased lung W/D (7.23 +/- 0.34, P < 0.05 vs. other groups), capillary occlusion, perivascular and alveolar hemorrhage, and septal disruption by mycelia. Bacteremia induced large increases in serum tumor necrosis factor-alpha (TNF) and interleukin-1 alpha within 1.5 h, but these cytokines remained low in CA animals, even at death. Neither survival nor ALI after EC or CA was altered by pentoxifylline, which attentuated TNF production, or by cyclooxygenase inhibition with ibuprofen. Thus, overall ALI severity correlated with physiological indices of pulmonary function, but ultrastructural changes correlated better with pathogen type than circulating cytokine or eicosanoid mediators. Whereas lethal bacteremia induced early cytokinemia and mild ALI with or without bacterial exotoxins, moderate ALI apparently was mediated by fungal exotoxins during lethal candidemia, which worsened during neutropenia due to enhanced mycelial proliferation.

An inhaled inducible nitric oxide synthase inhibitor reduces damage of Candida-induced acute lung injury

“…The present study demonstrated that inhalation of ONO-1714 reduced the tissue injury caused by peroxynitrite and suppressed the production of iNOS locally in the lung. Our results for the W/D ratio conflict with the finding of Okamoto et al (37) was injected into mice intravenously (1,26,32). Our results agree with those of a study by Kristof et al (23), using mice lacking the iNOS gene.…”

The Acute Inflammatory Response and Its Regulation

“…2 The general scheme of the inflammatory response is outlined in Figure 1. The inflammatory pathways in this particular model are very similar to events related to lung injury caused by ischemia, 3 by the presence of bacteria, 4 or by bacterial lipopolysaccharide. 5 These events trigger complement activation as well as activation of tissue macrophages.…”

Hypoxia and Fungal Pathogenesis: To Air or Not To Air?

“…Oxygen concentrations at sites of human fungal infection have not been measured directly in vivo, though hypoxemia is often described as part of the clinical picture associated with these infections, even in the lung, that may require invasive or noninvasive oxygen therapy (13,14,53,64,70,98). In addition, CO 2 production is directly coupled to oxygen consumption of eukaryotic cells and sites of hypoxia in vivo often contain increased levels of this gas, whose sensing has been linked to fungal virulence (31,67).…”