Enterokinase and IAV Infection

Cleavage and activation of hemagglutinin (HA) by trypsin-like proteases in influenza A virus (IAV) are essential prerequisites for its successful infection and spread. In host cells, some transmembrane serine proteases such as TMPRSS2, TMPRSS4 and HAT, along with plasmin in the bloodstream, have been reported to cleave the HA precursor (HA0) molecule into its active forms, HA1 and HA2. Some trypsinogens can also enhance IAV proliferation in some cell types (e.g., rat cardiomyoblasts). However, the precise activation mechanism for this process is unclear, because the expression level of the physiological activator of the trypsinogens, the TMPRSS15 enterokinase, is expected to be very low in such cells, with the exception of duodenal cells. Here, we show that at least two variant enterokinases are expressed in various human cell lines, including A549 lung-derived cells. The exogenous expression of these enterokinases was able to enhance the proliferation of IAV in 293T human kidney cells, but the proliferation was reduced by knocking down the endogenous enterokinase in A549 cells. The enterokinase was able to enhance HA processing in the cells, which activated trypsinogen in vitro and in the IAV-infected cells also. Therefore, we conclude that enterokinase plays a role in IAV infection and proliferation by activating trypsinogen to process viral HA in human cell lines

Characteristics of Respiratory Diseases in Older People

Abstract: Pneumonia among old people is the fourth leading cause of death, and its mortality has remained the same for the last 100 years despite development of antibiotics. We have elucidated the onset mechanism of pneumonia among old people and developed methods for its prevention. Its primary cause is considered to be cerebrovascular disorders in the basal ganglia, and absence of substance P causes sub-clinical aspiration, which in turn causes pneumonia. Prevention of pneumonia is now possible without the use of antibiotics by increasing substance P. As old people are immune-compromised by depressed state, measures against depression are important for preventing infections such as pneumonia and common cold. The older the patient is, the more intense the effect of gene appears. It was shown that elderly persons with L polymorphism of heme oxygenase (HO)-1 gene are more susceptible to pulmonary emphysema. Systemic examination of the elderly, particularly their physiological characteristic, is essential for treatment of elderly persons with respiratory diseases

Isolation of alveolar epithelial type II progenitor cells from adult human lungs

Resident stem/progenitor cells in the lung are important for tissue homeostasis and repair. However, a progenitor population for alveolar type II (ATII) cells in adult human lungs has not been identified. The aim of this study is to isolate progenitor cells from adult human lungs with the ability to differentiate into ATII cells. We isolated colony-forming cells that had the capability for self-renewal and the potential to generate ATII cells in vitro. These undifferentiated progenitor cells expressed surface markers of mesenchymal stem cells (MSCs) and surfactant proteins associated with ATII cells, such as CD90 and pro-surfactant protein-C (pro-SP-C), respectively. Microarray analyses indicated that transcripts associated with lung development were enriched in the pro-SP-C+/CD90+ cells compared with bone marrow-MSCs. Furthermore, pathological evaluation indicated that pro-SP-C and CD90 double-positive cells were present within alveolar walls in normal lungs, and significantly increased in ATII cell hyperplasias contributing to alveolar epithelial repair in damaged lungs. Our findings demonstrated that adult human lungs contain a progenitor population for ATII cells. This study is a first step toward better understanding of stem cell biology in adult human lung alveoli

Rhinovirus and airway allergy

Rhinoviruses cause the majority of common colds, which often provoke wheezing in patients with asthma. The precise mechanisms responsible for the rhinovirus infection-induced exacerbations of bronchial asthma remain uncertain. However, several reports have demonstrated airway hyperresponsiveness, increases in chemical mediators in airway secretions, such as kinin and histamine, and airway inflammation in patients with bronchial asthma after rhinovirus infection. Rhinovirus infection induces the accumulation of inflammatory cells in airway mucosa and submucosa, including neutrophils, lymphocytes and eosinophils. Rhinovirus affects the barrier function of airway epithelial cells and activates airway epithelial cells and other cells in the lung to produce proinflammatory cytokines, including various types of interleukins, granulocyte-macrophage colony stimulating factor and RANTES, and histamine. Rhinovirus also stimulates the expression of intercellular adhesion molecule-1 (ICAM-1) and low-density lipoprotein receptors in the airway epithelium, receptors for major and minor rhinoviruses. Rhinovirus infection is inhibited by treatment with soluble ICAM-1 and by the reduction of ICAM-1 expression in airway epithelial cells after treatment with either glucocorticoid or erythromycin. Both soluble ICAM-1 and erythromycin have been reported to reduce the symptoms of common colds. Herein, we review the pathogenesis and management of rhinovirus infection-induced exacerbation of bronchial asthma and the relationship between rhinovirus infection and airway allergy

A new strategy with proton pump inhibitors for the prevention of acute exacerbations in COPD

Acute exacerbations of chronic obstructive pulmonary disease (COPD), an acute worsening of respiratory symptoms, generally result in a poor prognosis. Successful prevention and management of such exacerbations is thus important for patient care. Viral infection, primarily with rhinovirus (RV), is the foremost cause of exacerbations in COPD patients. Proton pump inhibitors (PPIs) have been reported to inhibit RV infection in human airway epithelial cells in vitro . Furthermore, clinical trials of PPIs in patients with COPD resulted in a reduction in rates of both common cold and COPD exacerbations. In this review, we discuss the significance of COPD exacerbations, summarize a published trial of the effect of low-dose PPIs on COPD exacerbations, and postulate a mechanism for this effect

Inhibition of tracheal smooth muscle cell proliferation by phosphodiesterase inhibitors

Agents that increase intracellular cyclic 3',5'-adenosine monophosphate (cAMP), such as forskolin, prostaglandin (PG)E2, salbutamol and 8-bromo-cAMP, have been shownto inhibit the proliferation of airway smooth-muscle (ASM) cells in vitro. However, it has not yet been determined whether selective inhibitors of phosphodiesterase (PDE) isoenzymes III and IV that catalyze cAMPto 5'-adenosine monophosphate have the ability to inhibit ASM cell proliferation. To evaluate the effectsof PDE inhibitors on ASM cell proliferation, ASM cells isolated from bovine tracheae were cultured in the presence of fetal bovine serum (FBS), with or without a non-selective PDE inhibitor (theophylline), a selective PDE III inhibitor (cilostazol), and a selective PDE IV inhibitor (rolipram). The number of ASM cells cultured with 5% FBS was significantly reduced by the presence of theophylline at 10−3 and 3 × 10−4 mol/L, cilostazol at 10−5, 10−6 and 10−7 mol/L, and rolipram at 10−4 and 10−5 mol/L. The release of lactic dehydrogenase from ASM cells cultured with any concentration of these agents was not significantly different from that with medium alone. Inhibitors of PDE III and IV were demonstrated to have an inhibitory effect on ASM cell proliferation induced by FBS. Our results suggest the value of the further development of PDE inhibitors for the treatment of hyperplasia of ASM cells characteristic of airway remodeling, in addition to bronchospasm and airway inflammation, in bronchial asthma