A recent study estimated that somewhere between 9.2 million and 35.6 million influenza-related illnesses occur in the United States each year (1). The majority of patients present with upper respiratory tract symptoms, fatigue, myalgia, and sometimes fever, and “the flu” is usually self-resolving (2). However, more severe disease can occur, and there may be as many as 700,000 influenzarelated hospitalizations each year, resulting in up to 36,000 deaths. Cigarette smoking is a risk factor for severe influenza outcomes even in otherwise healthy patients, and this effect is exacerbated by comorbidities that are common in this population (3). Although influenza can result in acute, life-threatening, and even fatal disease in a subset of smokers, the potential long-term implications of infection for those who survive are not clear but could include more rapid disease progression and worsening of fibrosis. Unfortunately, however, this issue has not been studied in great detail to date.

In this issue of the Journal, Lee and colleagues (pp. 770–781) describe for the first time the impact of cigarette smoke (CS) exposure on lung fibroblast function after influenza infection (4). They show that exposure of mice to CS for only 2 weeks before infection with a dose of influenza A virus that causes severe (but not lethal) disease resulted in increased influenza severity. Furthermore, they find that CS exposure increases the amount of collagen and the number of fibroblasts present in the lungs after recovery from influenza. The latter effect is associated with a surge in production of active transforming growth factor b (TGF-b) in the lungs, which occurs after detectable viral replication has ceased. Moreover, antibody-mediated neutralization of this late TGF-b surge attenuates the fibrotic response in vivo. Most intriguingly, the authors demonstrate that lung-derived fibroblasts from CS-exposed and influenza-infected mice have an altered phenotype. When cultured, these cells showed more rapid proliferation, increased stress fiber formation, and higher expression of growth factors than did cells from influenza-infected mice exposed to room air. Overall, Lee and colleagues conclude that exposure to CS promotes increased fibrosis after influenza infection through its effects on the fibroblast.