Invariant natural killer T cells are found in low numbers in the airways of subjects with asthma, subjects with COPD, and controls.

-Severe acute respiratory syndrome (SARS) is a newly emerged disease that rapidly spread around the world. The disease originated in southern China and a novel coronavirus (SARS CoV) has been implicated as the causative organism. The path this virus took to set up human infection remains a mystery, though preliminary data point to origins in an animal reservoir. Nosocomial transmission of SARS CoV has been a striking feature in this epidemic. The clinical illness is similar to many acute respiratory infections, although a large proportion of patients show a rapid deterioration with respiratory distress towards the end of the second week of illness. The management principles are broadly similar to treating any community acquired pneumonia but the infection control measures take a pivotal role. There is no proven antiviral agent against SARS CoV. The most remarkable feature about the SARS epidemic was the speed with which the global community acted in a coordinated way to control it. HistoryPlagues are as certain as death and taxes. 3 Over the last century several important human microbes causing severe acute respiratory disease have emerged (Table 1). SARS CoV is not the first, and nor will it be the last of its kind. All these infections, with the exception of Legionnaires' disease, have one thing in common: the origin of the infective agent is in animals, either domestic or wild. Chlamydia pneumoniae and human metapneumovirus are examples of other new pathogens causing severe acute respiratory illness in which humans have always been the likely host. The source of SARS CoV remains to be determined.When reports of a mysterious respiratory illness began to emerge from southern China in late 2002, no one knew what caused it. Would history be repeated with a strain as deadly as the 1918 pandemic strain which killed up to 40 million people? Was this caused by a supervirulent strain of flu, as seemed to be suggested by the coincidence of two deaths due to H5N1 influenza? Even in mid-March, when outbreaks elsewhere in Asia caused the WHO to release its first ever global alert that shot SARS on to the world's news agenda, the pathogen remained unknown. 1 The infectiousness of the disease, its mode of transmission and death rate were also unclear. Health officials were not sure whether they were dealing with a troubling, but ultimately limited, threat or a global mass killer. 4 The earliest cases are now known to have occurred in mid-November 2002 in Guangdong Province, China. SARS was carried out into the world at large on 21 February 2003 when an infected medical doctor from Guangdong checked into a ninth floor room of a Hong Kong hotel. That single hotel floor n REVIEWS 152

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Chronic damage and repair of the bronchial epithelium are features of asthma. We have previously reported that ex vivo stimulation of normal bronchial epithelial cells with epidermal growth factor (EGF), a key factor of epithelial repair, enhances the mechanisms of neutrophil accumulation, thereby promoting neutrophil defences during acute injury but potentially enhancing inflammation in chronic airway diseases. We have now sought to (i) determine whether this EGF-dependent pro-neutrophil activity is increased in asthma, where EGF and its epithelial receptor are over-expressed, and (ii) elucidate some of the mechanisms underlying this asthmatic epithelial-neutrophil interaction. Primary bronchial epithelial cells (PBEC) from healthy subjects, mild asthmatics and moderate-to-severe asthmatics (Mod/Sev) were stimulated with EGF, a model that mimics a repairing epithelium. Conditioned culture media (EGF-CM) were assessed for neutrophil chemotactic and anti-apoptotic activities and inflammatory mediator production. EGF induced the epithelium to produce soluble mediators with neutrophil chemotactic (p<0.001) and pro-survival (p = 0.021) activities which were related to the clinical severity of asthma (trend p = 0.010 and p = 0.009, respectively). This was associated with enhanced IL-6, IL-8, GM-CSF and TNF-α release, and cytokine-neutralising experiments using EGF-CM from Mod/Sev asthmatics demonstrated a role for GM-CSF in neutrophil survival (p<0.001). Pre-treatment of neutrophils with specific inhibitors of the myeloid-restricted class I phosphatidylinositol-3-OH kinase (PI(3)K) isoforms showed that the EGF-CM from Mod/Sev asthmatics depended on the γ (p<0.021) but not δ isoforms, while neutrophil survival required multiple class I PI(3)Ks. The EGF-induced chemotactic, but not pro-survival activity, involved RhoA signaling in neutrophils (p = 0.012). EGF whose activity is upregulated in asthma induces ex vivo the epithelium from asthmatic patients to produce pro-neutrophil activities; these are related to asthma severity and, in moderate-to-severe asthmatics, involves class IB PI(3)Kγ signaling, providing a potential therapeutic target for neutrophilic forms of asthma.