Human mesenchymal stromal cells reduce influenza A H5N1-associated acute lung injury in vitro and in vivo

Influenza can cause acute lung injury. Because immune responses often play a role, antivirals may not ensure a successful outcome. To identify pathogenic mechanisms and potential adjunctive therapeutic options, we compared the extent to which avian influenza A/H5N1 virus and seasonal influenza A/H1N1 virus impair alveolar fluid clearance and protein permeability in an in vitro model of acute lung injury, defined the role of virus-induced soluble mediators in these injury effects, and demonstrated that the effects are prevented or reduced by bone marrow-derived multipotent mesenchymal stromal cells. We verified the in vivo relevance of these findings in mice experimentally infected with influenza A/H5N1. We found that, in vitro, the alveolar epithelium’s protein permeability and fluid clearance were dysregulated by soluble immune mediators released upon infection with avian (A/Hong Kong/483/97, H5N1) but not seasonal (A/Hong Kong/54/98, H1N1) influenza virus. The reduced alveolar fluid transport associated with down-regulation of sodium and chloride transporters was prevented or reduced by coculture with mesenchymal stromal cells. In vivo, treatment of aged H5N1-infected mice with mesenchymal stromal cells increased their likelihood of survival. We conclude that mesenchymal stromal cells significantly reduce the impairment of alveolar fluid clearance induced by A/H5N1 infection in vitro and prevent or reduce A/H5N1-associated acute lung injury in vivo. This potential adjunctive therapy for severe influenza-induced lung disease warrants rapid clinical investigation.Acute lung injury is a continuum of clinical and radiographic changes, terminating at its most severe, with acute respiratory distress syndrome. Infection with highly pathogenic avian influenza (HPAI) viruses of the H5N1 and more recent H7N9 subtypes often leads to acute lung injury whereas seasonal influenza viruses and the 2009 pandemic H1N1 influenza viruses do so more rarely. The underlying mechanisms of influenza-related acute lung injury remain unclear, and effective therapies are lacking. Viruses that are highly pathogenic to humans (e.g., H5N1 viruses) may differ intrinsically from the less pathogenic (LP) (e.g., seasonal H1N1) viruses in their replication competence, cell tropism, and/or cytokine dysregulation (1, 2). Early treatment of H5N1 disease with the antiinfluenza drug oseltamivir is helpful but does not ensure a favorable outcome (3). Thus, effective adjunctive therapies that do not compromise beneficial host defenses are needed (4).H5N1 (5) and H7N9 (6) influenza viruses target alveolar epithelial cells, which form the crucial gas exchange interface in the lung. These cells also help to maintain intraalveolar and intravascular fluid homeostasis by vectorial transport of sodium, chloride, and water from the apical to the basolateral surface of the alveolar epithelium [alveolar fluid clearance (AFC)]. Impaired AFC and increased alveolar protein permeability (APP) contribute to acute lung injury (7). Therapies that normalize alveolar fluid clearance are likely to be free of off-target effects, unlike immunomodulation, that may promote virus replication.Human bone marrow-derived multipotent mesenchymal stromal cells (MSCs) have applications in multiple clinical disorders, including sepsis, myocardial infarction, diabetes, and acute renal failure (8). Allogeneic MSC therapy has beneficial preclinical effects on endotoxin-, bacteria-, and ventilator-induced acute lung injury (9) via MSC secretion of the soluble paracrine growth factors angiopoietin-1 (Ang1) and keratinocyte growth factor (KGF) (9, 10). MSCs can also transfer mitochondria and microvesicles that modulate immunity and epithelial response to injury (11). Current clinical trials are testing MSCs as a therapy for sepsis and acute respiratory distress syndrome (12). However, little is known about the impact of MSCs on acute respiratory viral infections, including influenza, with the exception of a study in which MSCs failed to reduce influenza-induced lung injury in mice (13). Here, we showed that influenza A/H5N1 virus infection dysregulates AFC and APP in vitro by inducing infected cells to release soluble mediators that down-regulate alveolar sodium and chloride transporters. When we cocultured alveolar epithelium with MSCs, these injury mechanisms were prevented or reduced. We then treated mice infected with influenza A/H5N1 with MSCs and demonstrated a clinically significant reduction in lung pathology and increased survival in association with a modulation of these pathogenic mechanisms in vivo.     

Malignant Rhabdoid Tumor of the Floor of Mouth: First Reported Case in the Oral Cavity of an Adult

Malignant rhabdoid tumors (MRTs) are exceedingly rare lesions. To our knowledge, only 2 cases have been reported in the oral cavity, with both examples occurring in infants. The current case is the third reported case of MRT of the oral cavity and the first reported case to occur in an adult at this location. The following report describes the clinical, histologic and immunohistochemical features of this tumor.     

Direct sequencing of SARS-coronavirus S and N genes from clinical specimens shows limited variation

Severe acute respiratory syndrome-associated coronavirus (SARS-CoV) emerged, in November 2002, as a novel agent causing severe respiratory illness. To study sequence variation in the SARS-CoV genome, we determined the nucleic acid sequence of the S and N genes directly from clinical specimens from 10 patients--1 specimen with no matched SARS-CoV isolate, from 2 patients; multiple specimens from 3 patients; and matched clinical-specimen/cell-culture-isolate pairs from 6 patients. We identified 3 nucleotide substitutions that were most likely due to natural variation and 2 substitutions that arose after cell-culture passage of the virus. These data demonstrate the overall stability of the S and N genes of SARS-CoV over 3 months during which a minimum of 4 generations for transmission events occurred. These findings are a part of the expanding investigation of the evolution of how this virus adapts to a new host.     

Health-related quality of life among adolescents with eating disorders

Objective

Health-related quality of life (HRQoL) is an emerging area of research in eating disorders (EDs) that has not been examined in adolescents in detail. The aim of the current study is to investigate HRQoL in an adolescent ED sample, examining the impact of ED symptoms on HRQoL.

Methods

Sixty-seven treatment-seeking adolescents (57 females) with anorexia nervosa (AN), bulimia nervosa (BN), or eating disorder not otherwise specified (EDNOS) completed self-report measures of HRQoL and ED symptoms.

Results

Participants reported poorer HRQoL in mental health domains than in physical health domains. Disordered attitudes, binge eating, and compensatory behaviors were associated with poorer mental health HRQoL, and body dissatisfaction was associated with poorer physical health HRQoL.

Conclusion

The current study assessed HRQoL among adolescents with EDs, finding several consistencies with the literature on adults with EDs. Future research should compare adolescents and adults with EDs on HRQoL.