Idiopathic pulmonary fibrosis (IPF) is a devastating and fatal interstitial lung disease of unknown cause, characterized by continual progression and poor prognosis. The progression of IPF is thought to be due to recurring microinjuries to alveolar epithelial cells, in response to which, the lung launches an aberrant wound-healing program resulting in the continued accumulation of fibroblasts and deposition of collagen. Instead of appropriately healing the injured lung tissue, this results in organ fibrosis and eventual respiratory failure. There is abundant clinical and experimental data supporting the idea that IPF patients are uniquely susceptible to morbidity and mortality caused by respiratory infections. In particular, there is a clear link between the presence of potentially pathogenic bacteria within the lung and decreased survival in IPF patient populations. Bacterial genera Staphylococcus and Streptococcus have been associated with more rapid IPF disease progression and bacterial pathogens such as Staphylococcus aureus (methicillin-resistant and methicillin-sensitive) and Streptococcus pneumoniae are commonly isolated from the lungs of hospitalized IPF patients. In this study, we use Staphylococcal pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA) as a clinically relevant model to assess immune responses after bleomycin-induced lung fibrosis. We demonstrate that fibrotic mice infected with MRSA exhibit increased morbidity and mortality compared to uninfected fibrotic mice or mice treated with MRSA alone, mirroring clinical findings in IPF patients. In addition, we show that fibrotic lung injury induces a global downregulation of antibacterial responses resulting in impaired bacterial clearance in the lung. This defect corresponds with decreased recruitment of neutrophils and an altered lung inflammatory profile. We also find that neutrophils in fibrotic mice exhibit decreased phagocytosis and intracellular killing of MRSA, suggesting that fibrotic lung injury impairs the function of granulocytes. Taken together, this study demonstrates several mechanisms by which innate immune responses are suppressed after fibrotic lung injury. The present findings may provide a more complete understanding of why infection worsens prognosis in IPF.
