Inducible Expression of Inflammatory Chemokines in Respiratory Syncytial Virus-Infected Mice: Role of MIP-1α in Lung Pathology

Abstract

Lower respiratory tract disease caused by respiratory syncytial virus (RSV) is characterized by profound airway mucosa inflammation, both in infants with naturally acquired infection and in experimentally inocuRespiratory syncytial virus (RSV) is the major cause of serious lower respiratory disease in infancy and early childhood (5). Bronchiolitis, the more severe clinical manifestation of RSV infection, is characterized by necrosis and sloughing of the respiratory epithelium and plugging of the small bronchioles with fibrin and mucus. An intense peribronchial infiltration of mononuclear cells (lymphocytes and monocytes) occurs, with considerable edema (1, 8, 10). In addition, presence of the granule-associate cytotoxic proteins histamine, eosinophil cationic protein, and major basic protein in nasopharyngeal secretions and tracheobronchial aspirates suggests that RSV infection triggers the migration to the airways and activation of basophils and eosinophils (12,17,37,46). The evidence of an inverse correlation between the levels of these cytotoxic mediators and the degree of oxygen saturation in RSV-infected infants further underscores the critical role played by mucosal inflammation in the pathogenesis of RSV airway disease (12,45,46).The mouse model shows close similarity to the pathogenesis of RSV-induced lower airway disease in humans. In BALB/c mice, RSV rapidly replicates in the lungs after intranasal inoculation, and induces mononuclear cell infiltration around peribronchial and perivascular tissues (41) and objective plethysmographic signs of pulmonary dysfunction (i.e., increased respiratory rates and airway hyperresponsiveness) (29, 44).These pathophysiologic changes correlate with the amount of viral inoculum (44), consistent with the observation that more severe disease occurs in infected children who have higher concentrations of RSV in their secretions (4, 16).The mechanisms that regulate selective recruitment of inflammatory cells to the airways and their activation following RSV infection are still largely unknown. Similarly, virus-or host-specific factors that may influence these events have not been yet identified. Much of the cellular response at sites of tissue inflammation is controlled by gradients of chemotactic factors that direct leukocyte transendothelial migration and movement through the extracellular matrix. The composition of this cellular response is dependent upon the discrete target cell selectivity of these chemotactic molecules. Chemokines, a superfamily of small chemotactic cytokines, have emerged as central regulatory molecules in inflammatory, immune, and infectious processes of the lung (28). Chemokines have been primarily divided into two main subfamilies, CXC (␣) and CC (␤), upon their sequence homology and the position of the first two cysteine residues. In general, this subdivision is mirrored by the activity of these two chemokine groups on neutrophils (CXC) or monocytes, eosinophils, and basophils (CC). However, within the CXC subfamily, chemokines such as gamma inte...

Antioxidant Treatment Ameliorates Respiratory Syncytial Virus–induced Disease and Lung Inflammation

“…Multiple 4-m longitudinal cross-sections were stained with hematoxylin and eosin. The slides were analyzed and scored for cellular inflammation under light microscopy by a boardcertified pathologist, as previously described (21). The pathology score reported includes the number of abnormal perivascular and peribronchial regions divided by the total number of perivascular and peribronchial regions and are reported as the percentage of inflamed tissue.…”

“…We used a well-established clinical illness grading scale for mice to establish the severity of infection (0 ϭ healthy; 1 ϭ barely ruffled fur; 2 ϭ ruffled fur but active; 3 ϭ ruffled fur and inactive; 4 ϭ ruffled fur, inactive, and hunched; 5 ϭ dead) (21). In addition, daily determination of body weight was used to monitor the progression of disease over the experimental period.…”

“…Under light anesthesia, mice were inoculated intranasally with either sucrose-purified Hep-2 extracts (sham-infected) or sucrose-purified RSV at 1 ϫ 10 7 PFU, diluted in sterile phosphate-buffered saline (PBS) for a total inoculation volume of 50 l, as previously described (21). BHA was prepared by dissolving the right amount of compound in a 100-l volume of corn oil, which was administered by gavage, once a day, without anesthesia.…”

Respiratory Syncytial Virus Infection of Human Lung Endothelial Cells Enhances Selectively Intercellular Adhesion Molecule-1 Expression

“…For the synthesis of cDNA, prepared total RNA (2 g) was mixed with Moloney murine leukemia virus reverse transcriptase buffer (3 mM MgCl 2 , 75 mM KCl, 50 mM Tris-HCl; Life Technologies), 0.5 mM deoxyribonucleoside triphosphates (dNTP-Set; Life Technologies), 1 U/ l RNase inhibitor (Amersham), 4 U/ l Moloney murine leukemia virus reverse transcriptase (Life Technologies), and 2.0 ng of oligo(dT) [12][13][14][15][16][17][18] in a volume of 50 l. The synthesis of cDNA was done by heating at 37°C for 60 min. The cDNA was stored at Ϫ20°C.…”

Correlation of IFN-Inducible Protein 10 Levels in Sera with Disease Severity and Clinical Outcome of the Dengue Patients

“…It plays a key role in the trafficking and recruitment of effector T cells [2][3][4][5] . Furthermore, IP-10 is required for the resistance of the host to the primary DV infection in DV infected mice.…”