Previous studies have indicated that typical 2009 H1N1 viruses such as CA/04 bind only to a-2,6-linked sialic acid (SA) receptor [17] , but only the a-2,3-linked SA receptor is found in the mouse respiratory tract [20] . Therefore, such a typical 2009 H1N1 virus may not be able to induce ARDS in mice. In fact, we used CA/04 virus to induce ARDS in mice; however, animals inoculated with a high dose of CA/04 virus (10 6.5 pfu) only showed moderate respiratory symptoms, and no lethality was observed (unpublished data). It has been shown that 2009 H1N1 virus possessing a D222G mutation in hemagglutinin (HA) could increase the pathogenicity in mice [21, 22] and binding to the a-2,3 SA receptor [23] . Moreover, clinical data indicate that such variants are only associated with severe H1N1 human infection [24] . Therefore, we suggest that the variant possessing the D222G mutation in HA can induce ARDS in a mouse model. The virus used in the present study was isolated from swine in 2009, and sequence analysis revealed that all the eight genes of the isolate had a close relationship with the 2009 H1N1 influenza virus circulating in humans. Notably, the swine isolate, SD/09, had a D222G mutation in HA. Compared with CA/04 virus (LD 50 .10 6 pfu), SD/09 showed significantly increased virulence in mice, with an LD 50 of 10 2.25 pfu, which was nearly identical to that of the mouse-adapted strain A/Hong Kong/415742Md/09 (LD 50 = 10 2.2 pfu) [17, 21] . Mice infected i.n. with 10 2.5 pfu SD/ 09 virus showed obvious respiratory symptoms, including visually prominent signs of respiratory distress and abdominal respiration, with approximately 60% mortality between days 8 and 10 p.i. The lungs of virus-infected mice were highly edematous, which was also demonstrated by dramatically increased lung wet:dry weight ratio. Pathological changes presented a progressive pattern, typically diffuse alveolar damage, interstitial and alveolar edema, neutrophil and macrophage-dominant inflammatory cellular infiltration, and areas of hemorrhage and necrotizing bronchiolitis. Arterial blood gas saturation is a key parameter of ARDS in humans [25] . In the present mouse model, Pao 2 and Sao 2 of infected mice were significantly lower than in the control group from day 2 p.i., especially on day 8 p.i., where these parameters sharply decreased, and most virus-infected mice began to die. These changes in arterial blood gas demonstrated that most infected mice developed severe hypoxemia consistent with of the appearance of clinical signs and lung lesions of ARDS. Previous studies showed that mice infected with typical 2009 H1N1 virus only exhibited mild interstitial inflammatory infiltration and limited alveolitis [18, 21] , whereas severe lung damage was found in the SD/09-infected mice, including severe edema around the blood vessels and bronchiolitis, and extensive inflammatory accumulation from 4 to 8 days p.i. At 10 days p.i., the surviving mice developed an irreversible fibrosis involving collagen deposition in alveolar walls and spaces, which was similar to that observed in human ARDS patients with 2009 H1N1 infection [26] . Our histopathological results were consistent with ARDS induced by other influenza viruses. Mice infected with mouse-adapted virus of the A/Puerto Rico/8/34 (H1N1), or high pathogenic H5N1 virus also showed a progressive series of pathological changes from interstitial pneumonia to diffuse alveolar damage [13, 27] . However, in contrast to highly pathogenic H5N1 virus, mice infected with SD/09 virus did not show viral spread to extrapulmonary organs.