Myocarditis, often due to an aberrant immune response to infection, is a major cause of dilated cardiomyopathy. Microbial pattern recognition receptors, such as TLRs, orchestrate the cytokine and chemokine responses that augment or limit the severity of myocarditis. Using the mouse model of experimental autoimmune myocarditis (EAM), in which disease is induced by immunization with a heart-specific self peptide and the agonist to multiple TLRs, complete Freund's adjuvant, we found that increased serum concentrations of the chemokine CXCL1/KC correlated directly with decreased severity of myocarditis. To directly test whether CXCL1/KC caused the amelioration of myocarditis, we treated mice, after challenge with heart-specific self peptide, with exogenous recombinant CXCL1/KC. We found that the administration of recombinant mouse CXCL1/KC completely abrogated heart inflammatory infiltration and cardiomyocyte damage. Moreover, we show that TLR4 signaling is required to increase serum protein concentrations of CXCL1/KC in EAM, and we demonstrate that the administration of the TLR4 agonist LPS significantly decreased severity and prevalence of EAM and reduced the number of heart-specific self peptide reactive effector T cells. These findings reveal a novel function of CXCL1/KC in the context of organ-specific autoimmune disease that may prove useful for the treatment of inflammatory conditions that underlie human heart disease.
Recent research on the endothelium demonstrates complex interactions of endothelial cells with circulating immune cells, mediators such as cytokines, hormones and growth factors, and with the underlying parenchymal cells. These disparate interactions are involved in promotion of vascular development; maintenance of tissue homeostasis; and regulation of vascular repair. Injury to the endothelial monolayer is the sine qua non of organ dysfunction with endothelial repair the necessary first step needed for recovery. Thus, the capacity of the endothelium to regenerate itself is a key determinant of organ repair and survival after injury. Using the example of the lung, we will review the current state of knowledge regarding the importance of endothelium in the above mentioned processes with a focus on the role of stem cells, both endogenous (i.e., localized within the vessel wall) as well as exogenous (i.e., arriving in the vessel wall from distant sites such as the bone marrow) in promoting endothelial repair and regeneration. The subject of endothelial regeneration and the ways in which stem and progenitor cells contribute to this process has promise in treating vascular diseases. As we will highlight in this review, some questions have been addressed but many more remain and need to be addressed before cell-based therapies become a viable option.
Human embryonic stem cells differentiated under mesoderm-inducing conditions have important therapeutic properties in sepsis-induced lung injury in mice. Single cell suspensions obtained from day 7 human embryoid bodies (d7EBs) injected i.v. 1 hour after cecal ligation and puncture significantly reduced lung inflammation and edema as well as production of tumor necrosis factor-? and interferon-? in lungs compared with controls, whereas interleukin-10 production remained elevated. d7EB cell transplantation also reduced mortality to 50% from 90% in the control group. The protection was ascribed to d7EB cell interaction with lung resident CD11b+ cells, and was correlated with the ability of d7EB cells to reduce it also reduced production of proinflammatory cytokines by CD11+ cells, and to endothelial NO synthase-derived NO by d7EB cells, leading to inhibition of inducible macrophage-type NO synthase activation in CD11b+ cells. The protective progenitor cells were positive for the endothelial and hematopoietic lineage marker angiotensin converting enzyme (ACE). Only the ACE+ fraction modulated the proinflammatory profile of CD11b+ cells and reduced mortality in septic mice. In contrast to the nonprotective ACE-cell fraction, the ACE+ cell fraction also produced NO. These findings suggest that an ACE+ subset of human embryonic stem cell-derived progenitor cells has a highly specialized anti-inflammatory function that ameliorates sepsis-induced lung inflammation and reduces mortality.
To report 2 patients with systemic lupus erythematosus and typical shrinking lung syndrome (SLS) in which pleuritic chest pain was the predominant symptom. In addition, to record the prevalence of pleuritic chest pain in all reported cases of patients with SLS and diaphragmatic dysfunction.
Scleroderma sine scleroderma (ssSSc) is an occult form of systemic sclerosis that may cause diagnostic difficulties due to the absence of skin involvement. Delays in the diagnosis of ssSSc means lost opportunites to address and treat the often lethal involvement of internal organs such as the lungs and heart. In this systemic review we collected all published cases of ssSSc using EMBASE, MEDLINE, PubMed, and Web of Science from 1950 to present. Our purpose was to describe the range and frequency of the clinical manifestations of ssSSc. A total of 108 published cases of ssSSc were analyzed. Lung involvement was present in 66% of cases. Peripheral vascular system involvement was present in all patients whereas gastrointestinal manifestations were present in 82% of the cases. Overall the clinical presentation is subtle and heightened clinical awareness is required to facilitate prompt recognition and treatment.
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