Parenchymal Cell TNF Receptors Contribute to Inflammatory Cell Recruitment and Respiratory Failure in Pneumocystis carinii-Induced Pneumonia

Department of Pediatrics, University of Rochester Medical Center, Rochester, NY 14642, USA.
The Journal of Immunology (Impact Factor: 4.92). 08/2008; 181(2):1409-19. DOI: 10.4049/jimmunol.181.2.1409
Source: PubMed


The opportunistic organism Pneumocystis carinii (Pc) produces a life-threatening pneumonia (PcP) in patients with low CD4(+) T cell counts. Animal models of HIV-AIDS-related PcP indicate that development of severe disease is dependent on the presence of CD8(+) T cells and the TNF receptors (TNFR) TNFRsf1a and TNFRsf1b. To distinguish roles of parenchymal and hematopoietic cell TNF signaling in PcP-related lung injury, murine bone marrow transplant chimeras of wild-type, C57BL6/J, and TNFRsf1a/1b double-null origin were generated, CD4(+) T cell depleted, and inoculated with Pc. As expected, C57 --> C57 chimeras (donor marrow --> recipient) developed significant disease as assessed by weight loss, impaired pulmonary function (lung resistance and dynamic lung compliance), and inflammatory cell infiltration. In contrast, TNFRsf1a/1b(-/-) --> TNFRsf1a/1b(-/-) mice were relatively mildly affected despite carrying the greatest organism burden. Mice solely lacking parenchymal TNFRs (C57 --> TNFRsf1a/1b(-/-)) had milder disease than did C57 --> C57 mice. Both groups of mice with TNFR-deficient parenchymal cells had low bronchoalveolar lavage fluid total cell counts and fewer lavageable CD8(+) T cells than did C57 --> C57 mice, suggesting that parenchymal TNFR signaling contributes to PcP-related immunopathology through the recruitment of damaging immune cells. Interestingly, mice with wild-type parenchymal cells but TNFRsf1a/1b(-/-) hematopoietic cells (TNFRsf1a/1b(-/-) --> C57) displayed exacerbated disease characterized by increased MCP-1 and KC production in the lung and increased macrophage and lymphocyte numbers in the lavage, indicating a dysregulated immune response. This study supports a key role of parenchymal cell TNFRs in lung injury induced by Pc and a potential protective effect of receptors on radiosensitive, bone marrow-derived cells.

Download full-text


Available from: Gloria S Pryhuber
  • Source
    • "SP-A and SP-D are calcium-dependent lectins, and prominently produced by type II pneumocytes and Clara cells in injured lung [9]. PCP infection leads the accumulation of neutrophils and CD8 lymphocytes, and elicits the inflammatory mediator of macrophage inflammatory protein (MIP)-2, interleukin (IL)-8, and tumor necrosis factor (TNF)-α [10,11]. Mechansims of elevation of serum markers in PCP are thought that these mediators induce type II pneumocytes damages or hyperplasia, and this affects the elevations of KL-6, SP-A and SP-D on serum levels. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In patients with chronic respiratory disease, Pneumocystis jirovecii (P. jirovecii) colonization is observed, and may influence disease progression and systemic inflammation. Pneumocystis pneumonia causes interstitial changes, so making a diagnosis of PCP in patients who have interstitial pneumonia (IP) with P. jirovecii colonization is sometimes difficult based on radiography. This study investigated the prevalence of P. jirovecii colonization in IP patients and assessed pulmonary injury due to P. jirovecii colonization by measurement of serum markers (KL-6, SP-A, SP-D, and (1-->3) beta-D-glucan (beta-D-glucan)) and the peripheral lymphocyte counts, prospectively. A total of 75 patients with idiopathic pulmonary fibrosis (n = 29), collagen vascular-related interstitial pneumonia (n = 19), chronic bronchitis or pneumonia (n = 20), and Pneumocystis pneumonia (n = 7) were enrolled in this prospective study. P. jirovecii DNA was detected in sputum samples, while serum markers and the lymphocyte count were measured in the peripheral blood. IP patients (idiopathic pulmonary fibrosis and collagen vascular-related IP) who received oral corticosteroids had a high prevalence of P. jirovecii colonization (23.3%). In IP patients, oral corticosteroid therapy was a significant risk factor for P. jirovecii colonization (P < 0.05). Serum markers did not show differences between IP patients with and without P. jirovecii colonization. The beta-D-glucan level and lymphocyte count differed between patients with Pneumocystis pneumonia or P. jirovecii colonization. Serum levels of KL-6, SP-A, SP-D, and beta-D-glucan were not useful for detecting P. jirovecii colonization in IP patients. However, the serum beta-D-glucan level and lymphocyte count were useful for distinguishing P. jirovecii colonization from pneumocystis pneumonia in IP patients.
    Full-text · Article · May 2009 · BMC Infectious Diseases
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We determined the role of interleukin-1beta (IL-1beta) signaling on tumor necrosis factor alpha-induced (TNF-alpha) lung neutrophil influx as well as neutrophil chemoattractant macrophage inflammatory protein (MIP-2) and KC and soluble TNF-alpha receptor (TNFR) levels utilizing wildtype (WT), TNF receptor double knockout (TNFR1/TNFR2 KO), and IL-1beta KO mice after oropharyngeal instillation with TNF-alpha. A significant increase in neutrophil accumulation in bronchoalveolar lavage fluid (BALF) and lung interstitium was detected in the WT mice six hours after TNF-alpha exposure. This correlated with an increase in BALF MIP-2. In contrast, BALF neutrophil numbers were not increased by TNF-alpha treatment of IL-1beta KOs, correlating with a failure to induce BALF MIP-2 and a trend toward increased BALF soluble TNFR1. TNF-alpha-instillation increased lavage and serum KC and soluble TNFR2 irrespective of IL-1beta expression. These results suggest IL-1beta contributes, in part, to TNF-alpha-mediated, chemokine release, and neutrophil recruitment to the lung, potentially associated with altered soluble TNFR1 release into the BALF.
    Full-text · Article · Nov 2009 · Mediators of Inflammation
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pneumocystis jirovecii is the opportunistic fungal organism that causes Pneumocystis pneumonia (PCP) in humans. Similar to other opportunistic pathogens, Pneumocystis causes disease in individuals who are immunocompromised, particularly those infected with HIV. PCP remains the most common opportunistic infection in patients with AIDS. Incidence has decreased greatly with the advent of HAART. However, an increase in the non-HIV immunocompromised population, noncompliance with current treatments, emergence of drug-resistant strains and rise in HIV(+) cases in developing countries makes Pneumocystis a pathogen of continued interest and a public health threat. A great deal of research interest has addressed therapeutic interventions to boost waning immunity in the host to prevent or treat PCP. This article focuses on research conducted during the previous 5 years regarding the host immune response to Pneumocystis, including innate, cell-mediated and humoral immunity, and associated immunotherapies tested against PCP.
    Full-text · Article · Jan 2010 · Future Microbiology
Show more