American journal of respiratory cell and molecular biology
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Am. J. Respir. Cell Mol. Biol. · Jul 2003
Hypercapnic acidosis attenuates endotoxin-induced nuclear factor-[kappa]B activation.
Although permissive hypercapnia improves the prognosis of patients with acute respiratory distress syndrome, it has not been conclusively determined whether hypercapnic acidosis (HA) is harmful or beneficial to sustained inflammation of the lung. The present study was designed to explore the molecular mechanism of HA in modifying lipopolysaccharide (LPS)-associated signals in pulmonary endothelial cells. LPS elicited degradation of inhibitory protein kappaB (IkappaB)-alpha, but not IkappaB-beta, resulting in activation of nuclear factor (NF)-kappaB in human pulmonary artery endothelial cells. ⋯ Following the reduced NF-kappaB activation, HA suppressed the mRNA and protein levels of intercellular adhesion molecule-1 and interleukin-8, resulting in a decrease in both lactate dehydrogenase release into the medium and neutrophil adherence to LPS-activated human pulmonary artery endothelial cells. In contrast, HA did not inhibit LPS-enhanced neutrophil expression of integrin, Mac-1. Based on these findings, we concluded that hypercapnic acidosis would have anti-inflammatory effects essentially through a mechanism inhibiting NF-kappaB activation, leading to downregulation of intercellular adhesion molecule-1 and interleukin-8, which in turn inhibits neutrophil adherence to pulmonary endothelial cells.
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Am. J. Respir. Cell Mol. Biol. · Jul 2003
Recruitment of antigen-specific Th1-like responses to the human lung following bronchoscopic segmental challenge with purified protein derivative of Mycobacterium tuberculosis.
Although the mechanisms of specific immunity to Mycobacterium tuberculosis in humans are poorly understood, responses of Th1-like CD4+ T cells appear to be essential for protection. We hypothesized that healthy individuals displaying positive skin-test responses to purified protein derivative of M. tuberculosis (PPD) would have the capacity to mobilize M. tuberculosis-specific Th1 cells to the lung in response to bronchoscopic challenge with PPD. Local instillation of 0.5 tuberculin units of PPD was followed 48 h subsequently by bronchoalveolar lavage (BAL) of PPD-challenged and control segments. ⋯ In contrast, PPD-negative subjects did not develop local inflammation following PPD challenge. These findings indicate that bronchoscopic challenge with PPD results in recruitment of antigen-specific recall responses to the lung. This novel approach may be useful in clarifying the basis of local immunity against M. tuberculosis, and could serve more generally as a model of the development of Th1-like responses in the human lung.