Respiratory reovirus 1/L induction of diffuse alveolar damage: a model of acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a clinical syndrome that is characterized by diffuse alveolar damage usually secondary to an intense host inflammatory response of the lung to a pulmonary or extrapulmonary infectious or noninfectious insult. In this report we describe a unique animal model in which CBA/J mice infected with reovirus serotype 1, strain Lang develop ARDS. This model recapitulates the histopathological changes observed in human ARDS, which consists of the overlapping phases of exudation including the formation of hyaline membranes, regeneration, and healing via resolution and/or repair with fibrosis. While the consequences of a number of infectious and noninfectious insults in various animal systems have been developed as models of human ARDS, they are models of acute lung injury and are of short-term duration. Therefore, they do not recapitulate all of the clinical and pathological phases observed in human ARDS. Thus, study of the cellular and molecular factors involved in these distinct phases of the disease have been limited. Reovirus 1/L infection of CBA/J mice will allow investigations of the pathophysiology of ARDS as it progresses from the initial stages of edema and neutrophilia to fibrotic lesion development in late stages.     

Differential role for T cells in the development of fibrotic lesions associated with reovirus 1/L-induced bronchiolitis obliterans organizing pneumonia versus Acute Respiratory Distress Syndrome

Bronchiolitis obliterans organizing pneumonia (BOOP) and Acute Respiratory Distress Syndrome (ARDS) are two pulmonary diseases with fibrotic components. BOOP is characterized by perivascular/peribronchiolar leukocyte infiltration leading to the development of intra-alveolar fibrosis. ARDS is a biphasic disease that includes an acute phase, consisting of severe leukocyte infiltration, edema, hemorrhage, and the formation of hyaline membranes, and a chronic phase, which is characterized by persistent intra-alveolar and interstitial fibrosis. CBA/J mice infected with 1 x 10(6) plaque-forming units (pfu) reovirus 1/L develop follicular bronchiolitis and intra-alveolar fibrosis similar to BOOP. In contrast, CBA/J mice infected with 1 x 10(7) pfu reovirus 1/L develop histologic characteristics of ARDS including diffuse alveolar damage, hyaline membranes, and intra-alveolar fibrosis. In this report, we demonstrate a differential role for T lymphocytes in the development of fibrosis associated with BOOP versus ARDS. Neonatally thymectomized CBA/J mice infected with 1 x 10(7) pfu (ARDS) reovirus 1/L still develop the hallmark characteristics of ARDS, including a severe viral pneumonia with cellular infiltrates comprised mainly of macrophages and neutrophils, hyaline membrane formation, and hemorrhage during the acute phase of the disease and persistent intra-alveolar fibrosis during the chronic phase of the disease. In contrast, neonatally thymectomized CBA/J mice infected with 1 x 10(6) pfu (BOOP) reovirus 1/L do not develop intra-alveolar fibrosis associated with BOOP. Therefore, while T cells are necessary for the development of intraluminal fibrosis associated with BOOP, they are not necessary for the development of intraluminal fibrosis associated with ARDS. Furthermore, we suggest that interferon-gamma plays a key role in the fibrotic process and that elevated levels of interferon-gamma are associated with a continuum from least to more severe fibrosis.     

Respiratory reovirus 1/L induction of intraluminal fibrosis, a model of bronchiolitis obliterans organizing pneumonia, is dependent on T lymphocytes

Bronchiolitis obliterans organizing pneumonia (BOOP) is a clinical syndrome characterized by perivascular/peribronchiolar leukocyte infiltration leading to the development of intraalveolar fibrosis. We have developed an animal model of BOOP where CBA/J mice infected with 1 x 10(6) plaque-forming units (PFU) reovirus 1/L develop follicular bronchiolitis and intraalveolar fibrosis similar to human BOOP. In this report, we demonstrate a role for T cells in the development of intraluminal fibrosis associated with BOOP. Corticosteroid treatment of reovirus 1/L-infected mice both inhibited the development of fibrotic lesions when administered early in the time-course and promoted the resolution of fibrotic lesions when corticosteroid administration was delayed. Further, the depletion of either CD4(+) or CD8(+) T cells before reovirus 1/L infection also inhibited fibrotic lesion development. Both corticosteroid treatment and depletion of CD4(+) or CD8(+) T cells also resulted in decreased expression of the proinflammatory and profibrotic cytokines, interferon (IFN)-gamma and monocyte chemoattractant protein-1 (MCP-1). Further, treatment of mice with a neutralizing monoclonal antibody to IFN-gamma also significantly inhibited the development of fibrosis. Taken together, these results suggest a significant role for T cells in the development of reovirus 1/L-induced BOOP fibrotic lesions in CBA/J mice and suggests that T(H)1-derived cytokines, especially IFN-gamma, may play a key role in fibrotic lesion development.     

NOX1 is responsible for cell death through STAT3 activation in hyperoxia and is associated with the pathogenesis of Acute Respiratory Distress Syndrome

Reactive oxygen species (ROS) contribute to alveolar cell death in Acute Respiratory Distress Syndrome (ARDS) and we previously demonstrated that NOX1-derived ROS contributed to hyperoxia-induced alveolar cell death in mice. The study investigates whether NOX1 expression is modulated in epithelial cells concomitantly to cell death and associated to STAT3 signaling in the exudative phase of ARDS. In addition, the role of STAT3 activation in NOX1-dependent epithelial cell death was confirmed by using a lung epithelial cell line and in mice exposed to hyperoxia. NOX1 expression, cell death and STAT3 staining were evaluated in the lungs of control and ARDS patients by immunohistochemistry. In parallel, a stable NOX1-silenced murine epithelial cell line (MLE12) and NOX1-deficient mice were used to characterize signalling pathways. In the present study, we show that NOX1 is detected in alveolar epithelial cells of ARDS patients in the exudative stage. In addition, increased alveolar epithelial cell death and phosphorylated STAT3 are observed in ARDS patients and associated with NOX1 expression. Phosphorylated STAT3 is also correlated with TUNEL staining. We also confirmed that NOX1-dependent STAT3 activation participates to alveolar epithelial cell death. Silencing and acute inhibition of NOX1 in MLE12 led to decreased cell death and cleaved-caspase 3 induced by hyperoxia. Additionally, hyperoxia-induced STAT3 phosphorylation is dependent on NOX1 expression and associated with cell death in MLE12 and mice. This study demonstrates that NOX1 is involved in human ARDS pathophysiology and is responsible for the damage occurring in alveolar epithelial cells at least in part via STAT3 signalling pathways.     

Involvement of high mobility group box 1 and the therapeutic effect of recombinant thrombomodulin in a mouse model of severe acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is accompanied by severe lung inflammation induced by various diseases. Despite the severity of the symptoms, therapeutic strategies have been ineffective. High mobility group box 1 (HMGB1), which was identified originally as a DNA binding protein, has been proposed as a mediator of acute lung injury. In addition to its anti‐coagulant activity, recombinant thrombomodulin (rTM) possesses an ability to suppress the inflammatory response through neutralizing HMGB1. T regulatory (T_reg) cells in the lungs are reported to modify innate immune responses during resolution of acute lung injury. In the present study, we investigated the therapeutic effect of rTM, and the contribution of T_reg cells to this effect, in a mouse model of severe ARDS. C57BL/6 mice received sequential intratracheal administration of α‐galactosylceramide (α‐GalCer) and lipopolysaccharide (LPS), which resulted in the development of severe ARDS. HMGB1 levels in the lungs increased to a higher level in ARDS mice compared to those in mice treated with LPS alone. HMGB1 was expressed in the infiltrating neutrophils and macrophages in lungs. T_reg cells were reduced significantly in the lungs of ARDS mice compared to those in mice treated with LPS alone. rTM administration prolonged the survival time and ameliorated the development of ARDS, which was associated with increased T_reg cells and synthesis of interleukin (IL)‐10 and transforming growth factor (TGF)‐β in the lungs. These results suggest that HMGB1 is involved in the development of severe ARDS and rTM shows therapeutic effects through promoting the accumulation of T_reg cells at the inflammatory sites.     

Heterogeneous expression of cell adhesion molecules by endothelial cells in ARDS

ARDS (acute respiratory distress syndrome) can be associated with septic shock and multiple organ failure caused by an uncontrolled systemic inflammatory response to Gram-negative bacterial infection. While in animal models the key role of the endothelial adhesion molecules ICAM-1, E-selectin, and VCAM in ARDS has been extensively studied, there are scarcely any corresponding pathomorphological studies of human lung tissue. Hence, little is known about whether there is a comparable, or even heterogeneous, expression pattern of these molecules in the human pulmonary vasculature. This study was therefore undertaken to investigate the immunohistochemical expression of the constitutively expressed PECAM (CD31) and the inducible molecules ICAM-1, E-selectin, and VCAM in ARDS lungs from patients who had died in septic shock induced by Gram-negative bacteria. While in all specimens (ARDS and normal lungs) there was homogeneous strong expression of PECAM in all vessels, ICAM-1 was clearly up-regulated in ARDS lungs. E-selectin and VCAM were not expressed by endothelial cells (ECs) in normal lungs, but in ARDS lungs there was strong expression of both molecules in larger vessels, while in the capillaries there was only mosaic-like weak expression of a few ECs. This immunohistochemical investigation demonstrates the induction and up-regulation of adhesion molecules in human ARDS lungs, comparable to that described in animal models. There is also markedly heterogeneous expression of E-selectin and VCAM, indicating toporegional differences in the function of pulmonary ECs.     

Acute respiratory distress syndrome induced by H9N2 virus in mice

H9N2 avian influenza viruses have repeatedly caused infections in swine and humans in some countries. The purpose of the present study was to evaluate the pulmonary pathology caused by H9N2 viral infection in mice. Six- to eight-week-old BALB/c mice were infected intranasally with 1 × 10⁴ MID₅₀ of A/Chicken/Hebei/4/2008(H9N2) virus. Clinical signs, pathological changes and viral replication in lungs, arterial blood gas, and cytokines in bronchoalveolar lavage fluid (BALF) were observed at different time points after infection. A control group was infected intranasally with noninfectious allantoic fluid. H9N2-infected mice exhibited severe respiratory syndrome, with a mortality rate of 60%. Gross observations showed that infected lungs were highly edematous. Major histopathological changes in infected lungs included diffuse pneumonia and alveolar damage, with neutrophil-dominant inflammatory cellular infiltration, interstitial and alveolar edema, hemorrhage, and severe bronchiolitis/peribronchiolitis. In addition, H9N2 viral infection resulted in severe progressive hypoxemia, lymphopenia, and a significant increase in neutrophils, tumor necrosis factor-α and interleukin-6 in BALF. The features described above satisfy the criteria for acute respiratory distress syndrome (ARDS). Our data show that H9N2 viral infection resulted in ARDS in mice, and this may facilitate studies of the pathogenesis of future potential H9N2 disease in humans.     

Prolonged induction of IL-8 gene expression in a human fibroblast cell line infected with reovirus serotype 1 strain Lang

Viruses which infect mucosal surfaces commonly infect these particular anatomical sites based on both the virion structure and the interaction of the virus with a particular microenvironment. We infected a human lung epithelial cell line, a human gut epithelial cell line, and a human lung fibroblast cell line with reovirus 1/L to explore how this natural isolate of both the lung and the gut may interact with mucosal surfaces. While reovirus infection of the gut and lung epithelial cell lines was lytic, a chronic infection was established in the human lung fibroblast cell line. All three cell lines also produced interleukin-8 (IL-8) after infection with reovirus 1/L, and IL-8 production was not dependent upon viral replication. A prolonged production of IL-8 was observed in the chronically infected lung fibroblast cell line, suggesting that this mucosal population may be involved in the generation of inflammatory responses after the resolution of the initial lytic infection of the epithelium. These studies provide an in vitro model system for analyzing the interaction of reovirus 1/L with resident mucosal cell populations.     

Respiratory syncytial virus infection in a murine model of cystic fibrosis

Viral respiratory infections play an important role in the development and progression of pulmonary disease in cystic fibrosis (CF). The CF mouse model provides a tool to examine the relationship between the cystic fibrosis transmembrane conductance regulator (CFTR) defect and lung disease. This work investigates the cellular response to a common viral pathogen, respiratory syncytial virus (RSV) in the lung of CF mice. RSV was administered by intranasal inoculation of CFTR(tm1Unc)-Tg(FABPCFTR)1Jaw/J (CFTR-/-) and control mice. At day 5 post infection, viral titers, bronchoalveolar fluid nitrate levels (BALF) cell and differential counts, histology and studies on airway mechanics were performed. CFTR-/- mice had an impaired ability to clear RSV. This was associated with an exaggerated inflammatory response (increased lymphocytes and neutrophils) in BALF of RSV-infected CFTR-/- mice and a decreased ability to generate nitric oxide (NO) (measured as BAL nitrate). Lung histopathology of RSV-infected CFTR-/- mice demonstrated increased inflammation compared to RSV (-) CFTR-/- and control mice (regardless of RSV treatment). The airway response to methacholine was increased by RSV infection in CF mice when compared to controls. The CFTR-/- mouse exhibits an aberrant response to RSV infection. This model should be useful in providing further mechanistic information on the biology of respiratory viruses in mammalian models, and provide new insights into the pathogenesis of airway inflammation in patients with CF.     

Pulmonary tuberculosis in BALB/c mice with non-functional IL-4 genes: changes in the inflammatory effects of TNF-alpha and in the regulation of fibrosis

In BALB/c mice, as in man, progressive pulmonary tuberculosis is accompanied by increasing expression of IL-4. Therefore we have used BALB/c mice with disrupted IL-4 genes (IL-4(-/-)) to investigate the role of IL-4 in pulmonary tuberculosis, with particular emphasis on the toxicity of TNF-alpha and on fibrosis, both of which are neglected aspects of human tuberculosis. Delayed-type hypersensitivity (DTH) sites in IL-4(+/+) mice were sensitive to the toxicity of locally injected TNF-alpha, whereas DTH sites in IL-4(-/-) mice were not. However, intravenous administration of IL-4 to IL-4(-/-) mice restored the sensitivity of the DTH sites to pro-inflammatory effects of TNF-alpha. In late disease, the lungs of IL-4(+/+) mice expressed low IFN-gamma, but high TGF-beta and IL-4, correlating with fibrosis, detected as a high hydroxyproline content. In contrast, TGF-beta peaked 7 days after infection in the lungs of the IL-4(-/-) mice, and then fell to very low levels in the late disease, while IFN-gamma remained high. Accordingly, hydroxyproline content was reduced in infected IL-4(-/-) mice compared to IL-4(+/+) controls. In conclusion, the findings suggest that IL-4 has modestly detrimental effects on the antibacterial efficacy of the Th1 response, and larger effects on the toxicity of TNF-alpha, and on fibrosis.     

Immunoregulatory abnormalities induced by experimental reovirus infection: functional alterations in T-cell subpopulations

A primary anti-sheep red blood cell (SRBC) plaque assay system was used to analyze the effect of reovirus infection on immunoregulatory T-cells. A decrease in the plaque-forming cell (PFC) response of splenic lymphocytes was observed within 24 hr of infection with 10(9) or 10(11) particles of reovirus type 1 or reovirus type 3 and persisted for more than 7 days. In coculture experiments, T-cells from infected mice were found to produce less help to control B-cells and to suppress helper function mediated by control T-cells. This suppression did not require the presence of an Lyt1,2,3 cell. In addition, isolated Lyt1 cells from reovirus-inoculated mice provided less help than did Lyt1 cells from normal controls. These abnormalities were more marked following inoculation with reovirus type 3 than with type 1. Live virus was not required for these effects, as T-cells from mice inoculated with ultraviolet (uv)-inactivated reovirus when added to normal B-cells reproduced the effects of infection with live virus. Furthermore, these changes were not the result of alterations in the percentages or numbers of distinct Lyt-bearing T-cell subpopulations in the spleens of inoculated mice. Thus, humoral hyporesponsiveness following reovirus infection of adult mice is associated both with active T-cell suppression of B-cell help and with decreased help mediated by the Lyt1 subset.     

Interactions of preimplantation mouse embryos with reovirus serotypes 1 and 3

Mouse two-cell embryos were infected in vitro with reovirus serotypes 1/Lang and 3/Dearing, and the embryos were either implanted into pseudopregnant mice or observed in vitro for cytopathic effects. The reovirus serotypes 1/Lang and 3/Dearing differed in their capacity to kill embryos in vitro and in vivo: when embryos were infected in vitro with reovirus serotype 1/Lang and then transferred to foster mothers, pups resulted only at multiplicities of infection of a few particles per embryo. In contrast, infection of embryos with as much as 6 X 10(4) reovirus type 3 particles per embryo resulted in viable pups. In vitro, reovirus serotype 1/Lang was more virulent than serotype 3/Dearing. The infection of ovum with reovirus offers a unique model for the study of congenital infection and should yield important information concerning the molecular basis of virus virulence to maturing fetuses.     

Respiratory syncytial virus-induced CCL5/RANTES contributes to exacerbation of allergic airway inflammation

Severe respiratory syncytial virus (RSV) infection has a significant impact on airway function and may induce or exacerbate the response to a subsequent allergic challenge. In a murine model combining early RSV infection with later cockroach allergen (CRA) challenge, we examined the role of RSV-induced CCL5/RANTES production on allergic airway responses. RSV infection increased CCL5 mRNA and protein levels, peaking at days 8 and 12, respectively. Administration of CCL5 antiserum during days 0-14 of the RSV infection did not significantly alter viral protein expression when compared to mice treated with control serum. In mice receiving the combined RSV-allergen challenge, lungs collected on day 22 exhibited significantly increased numbers of CD4- and CD8-positive T cells. This increase in T cell numbers was not observed in mice receiving alpha-CCL5. On day 43, peribronchial eosinophilia and leukotriene levels were increased in RSV-allergen mice. Pretreatment with CCL5 antiserum resulted in decreased recruitment of inflammatory cells to bronchoalveolar and peribronchial regions of the lungs and these reductions were associated with a reduction in both T cell recruitment into the bronchoalveolar space, leukotriene release and chemokine generation. Thus, CCL5 released during RSV infection has a significant effect on the inflammatory response to subsequent allergic airway challenges.     

FATAL cryptococcal meningitis in a child with hyper-immunoglobulin M syndrome,with an emphasis on the agent

Following a fatal case of Cryptococcus neoformans meningitis in a child with X-linked hyper-immunoglobulin M syndrome (XHIGM), we evaluated the fungal isolate in an experimental infection in a mouse model with respect to microbiology, epidemiology, virulence and response to therapy. The minimum inhibitory concentrations for antifungals in the susceptibility test were 0.5 mg/L for amphotericin B, 4.0 mg/L for fluconazole and 0.12 mg/L for voriconazole. Evaluation of pathogenicity by means of an experimental infection in BALB/c mice showed that fungus isolated from the blood and cerebrospinal fluid of the child was able to disseminate, reaching the spleen, lungs and brain, where it caused significant macroscopic alterations in the size and texture of each organ. Treatment of infected mice with amphotericin B reduced the fungal load in the spleen and lungs, but not in the brain.     

Mouse strain differences in the chemokine response to acute lung infection with a murine gammaherpesvirus

Numerous mouse strain-based differences in the immune response and in susceptibility to numerous pathogens have been described, but it is not known if these differences extend to chemokine responses to viral infection of the lungs. To define mouse strain-based differences in the host chemokine response and susceptibility to infection with murine gammaherpesvirus-68 (MHV-68), we compared the induced chemokine response to MHV-68 infection in the lungs of BALB/c and C57BL/6 mice at 1-15 days post-infection. CC and CXC chemokines were induced in both BALB/c and C57BL/6 following infection but the level of chemokine induction was significantly higher in the BALB/c mice for all chemokines measured. In addition, interferon-gamma (IFN-gamma) was also induced to a significantly higher level in the lungs of BALB/c infected mice compared to C57BL/6 mice. Interestingly, viral gene expression was lower in the lungs of C57BL/6 mice during the acute phase of replication. Titers of infectious virus were also greater in BALB/c lungs, although they did not achieve statistical significance. In contrast, latent viral load in the spleen, as measured by quantitative real-time PCR, did not significantly differ between mouse strains, suggesting that the establishment of latency is not affected by the amount of virus present during acute infection. This data suggests that robust chemokine response and expression of IFN-gamma in the lungs of infected BALB/c mice does not correlate with increased resistance to infection. In addition, the significant differences in chemokine responses observed will be important factors to consider in future studies of viral pathogenesis using mouse models.     

盐皮质激素受体在博来霉素诱导的实验性肺纤维化中的作用*

 目的：研究盐皮质激素受体（MR）在博来霉素诱导的实验性肺纤维化进展过程中的作用及机制。方法：将126只6～8周龄雄性C57BL/6小鼠随机分为对照组、博来霉素组和MR阻断剂螺内酯干预组,气管内一次性滴注博来霉素(2.5 mg/kg)溶液建立实验性小鼠肺纤维化模型,螺内酯干预组每天按螺内酯20 mg/kg经灌胃给药。于术后12 h、1 d、2 d、3 d、7 d、14 d和28 d处死小鼠,采用HE染色和Masson染色观察肺组织病理学变化及纤维化程度,采用real-time PCR检测各组肺组织中胶原1(Col1)、Col3、转化生长因子β(TGF-β)、单核细胞趋化蛋白1（MCP-1）及MR mRNA的表达水平。结果：（1）与对照组小鼠相比,博来霉素组及螺内酯干预组小鼠在滴注博来霉素后经历了典型的急性炎症期（12 h～3 d）、纤维化进展期（14 d）和纤维化晚期（28 d）。阻断MR下调早期炎症反应并减轻了纤维化程度。（2）螺内酯干预可以有效降低MR mRNA表达水平;阻断MR在急性炎症期显著下调MCP-1 mRNA的表达,在14 d显著下调TGF-β、Col1和Col3 mRNA表达水平。结论：(1）阻断MR可以明显减轻博来霉素诱导的肺纤维化程度;(2）阻断MR可能通过在急性炎症期调节MCP-1和TGF-β的表达,减轻炎症反应,并在纤维化进展期,下调TGF-β的表达,从而抑制肺纤维化的进展。     

Chemokine production and leukocyte recruitment to the lungs of Paracoccidioides brasiliensis-infected mice is modulated by interferon-gamma

Chemokines and chemokine receptors play a role in cell recruitment during granulomatous inflammatory reactions. Here, we evaluated the expression of chemokines and chemokine receptors and their regulation by IFN-gamma in the course of Paracoccidioides brasiliensis (Pb) infection in mice. We found an association between KC and MIP-1alpha (CCL3) production and neutrophil infiltration in the lungs of Pb-infected mice during the early acute phase of infection. High levels of RANTES/CCL5, MCP-1/CCL2, IP-10/CXCL10, and Mig/CXCL9 simultaneously with mononuclear cell infiltration in the lungs was found. In the absence of IFN-gamma (GKO mice) we observed increased production of KC and MIP-1alpha and chronic neutrophilia. Moreover, we found a change in the chemokine receptor profiles expressed by wild-type (WT) versus GKO animals. Increased expression of CXCR3 and CCR5, and low levels of CCR3 and CCR4 were observed in the lungs of Pb-infected WT mice, whereas the opposite effect was observed in the lungs of GKO mice. Consistent with these results, infected cells from WT mice preferentially migrated in response to IP-10 (CXCR3 ligand), while those from GKO mice migrated in response to eotaxin/CCL11 (CCR3 ligand). These results suggest that IFN-gamma modulates the expression of chemokines and chemokine receptors as well as the kind of cells that infiltrate the lungs of Pb-infected mice.     

人感染高致病性禽流感病毒H5N1的病理学观察

目的 观察人感染高致病性禽流感病毒H5N1后各主要脏器的病理改变.方法 按传染病尸体解剖要求对2例死亡病例系统解剖,并获得心、肝、脾、肺和肾等主要脏器,对1例重症患者行肺大泡切除术,组织常规HE和免疫组织化学染色,光学显微镜下观察.结果 2例肺组织主要呈弥漫性肺泡损伤改变.早期呈渗出性改变,肺泡上皮坏死脱落,肺泡腔内见大量均匀粉染渗出液伴广泛透明膜形成.中晚期主要呈增生性和纤维化性改变,肺泡上皮和支气管上皮增生,肺泡腔内渗出物和肺间质纤维化.1例在慢性支气管扩张症基础上伴弥漫性肺泡损伤和肺间质纤维化.免疫器官改变:全身淋巴组织萎缩伴活跃的噬血现象.其他脏器病变:1例心脏有间质性心肌炎;1例肾脏有急性肾小管坏死;1例有脑水肿伴脑实质内神经细胞嗜酸性变,轴突肿胀,粗细不均.脑室旁见灶状坏死.1例孕妇胎盘内多灶状滋养叶细胞坏死伴营养不良性钙化,有急性坏死性蜕膜炎.胚胎肺脏有肺水肿和肺炎改变.结论 人感染高致病性禽流感病毒H5N1后首先出现呼吸系统症状,广泛弥漫性肺泡损伤致低氧血症是病理学基础,患者最终因多器官功能衰竭致呼吸、循环衰竭死亡.     

Role of endoplasmic reticulum stress in age-related susceptibility to lung fibrosis

The incidence of idiopathic pulmonary fibrosis (IPF) increases with age. The mechanisms that underlie the age-dependent risk for IPF are unknown. Based on studies that suggest an association of IPF and γherpesvirus infection, we infected young (2-3 mo) and old (≥18 mo) C57BL/6 mice with the murine γherpesvirus 68. Acute murine γherpesvirus 68 infection in aging mice resulted in severe pneumonitis and fibrosis compared with young animals. Progressive clinical deterioration and lung fibrosis in the late chronic phase of infection was observed exclusively in old mice with diminution of tidal volume. Infected aging mice showed higher expression of transforming growth factor-β during the acute phase of infection. In addition, aging, infected mice showed elevation of proinflammatory cytokines and the fibrocyte recruitment chemokine, CXCL12, in bronchoalveolar lavage. Analyses of lytic virus infection and virus reactivation indicate that old mice were able to control chronic infection and elicit antivirus immune responses. However, old, infected mice showed a significant increase in apoptotic responses determined by in situ terminal deoxynucleotidyl transferase dUTP nick end labeling assay, levels of caspase-3, and expression of the proapoptotitc molecule, Bcl-2 interacting mediator. Apoptosis of type II lung epithelial cells in aging lungs was accompanied by up-regulation of endoplasmic reticulum stress marker, binding immunoglobulin protein, and splicing of X-box-binding protein 1. These results indicate that the aging lung is more susceptible to injury and fibrosis associated with endoplasmic reticulum stress, apoptosis of type II lung epithelial cells, and activation of profibrotic pathways.     

Respiratory syncytial virus infection provokes airway remodelling in allergen-exposed mice in absence of prior allergen sensitization

Background The mechanisms underlying exacerbation of asthma induced by respiratory syncytial virus (RSV) infection have been extensively studied in human and animal models. However, most of these studies focused on acute inflammation and little is known of its long-term consequences on remodelling of the airway tissue.
Objective The aim of the study was to use a murine model of prolonged allergen-induced airway inflammation to investigate the effect of RSV infection on allergic airway inflammation and tissue remodelling.
Methods We subjected mice to RSV infection before or during the chronic phase of airway challenges with OVA and compared parameters of airway inflammation and remodelling at the end-point of the prolonged allergen-induced airway inflammation protocol.
Results RSV infection did not affect the severity of airway inflammation in any of the groups studied. However, RSV infection provoked airway remodelling in non-sensitized, allergen-challenged mice that did not otherwise develop any of the features of allergic airways disease. Increased collagen synthesis in the lung and thickening of the bronchial basal membrane was observed in non-sensitized allergen-challenged mice only after prior RSV infection. In addition, fibroblast growth factor (FGF)-2 but not TGF-β₁ was increased in this group following RSV infection.
Conclusion Our data show for the first time that RSV infection can prime the lung of mice that are not previously systemically sensitized, to develop airway remodelling in response to allergen upon sole exposure via the airways. Moreover, our results implicate RSV-induced FGF-2 in the remodelling process in vivo .