Acute lower respiratory tract infections are a persistent and pervasive public health problem. They cause a greater burden of disease worldwide than human immunodeficiency virus infection, malaria, cancer, or heart attacks. 1 In the United States, they cause more disease and death than any other infection, and there has been little change in mortality due to respiratory tract infection for more than five decades. 1,2 The outcome of an acute lower respiratory tract infection depends on the virulence of the organism and the inflammatory response in the lung. When small numbers of low-virulence microbes are deposited in the lungs, an effective defense can be mounted by resident innate immune defenses, such as the mucociliary escalator, antimicrobial proteins in airway surface liquid, and alveolar macrophages. In contrast, numerous or more virulent microbes elicit an inflammatory response. Although this response serves to reinforce innate immunity and is essential to rid the lungs of microbes, it contributes directly to lung injury and abnormal pulmonary function. This article reviews our current understanding of inflammatory responses in infected lungs, emphasizing recent advances and gaps in knowledge. Much of the information originates from animal experiments; studies with human volunteers and patient-derived data are included when appropriate and available. INFLAMMATION AND INNATE IMMUNITY Acute inflammation features the accumulation of neutrophils and a plasma exudate outside of blood vessels. In the pulmonary capillaries of uninfected lungs, these blood contents are normally separated from the alveolar air by less than 1 µm, the thinnest interface between the blood and the environment. The trapping of neutrophils in these capillaries, which is the result of geometric and biophysical constraints, 3 increases their quantity per volume of blood by approximately 50 times as compared with other blood vessels, forming a marginated pool of neutrophils that is ready to respond when needed. During pulmonary infection, neutrophils migrate out of the pulmonary capillaries and into the air spaces. 4 Elie Metchnikoff, the discoverer of phagocytosis, considered neutrophils (or microphages, as he called them) to be "the defensive cells par excellence against microorganisms." 5 After phagocytosis, neutrophils kill ingested microbes with reactive oxygen species (e.g., hypochlorite), antimicrobial proteins (e.g., bactericidal permeabilityinducing protein and lactoferrin), and degradative enzymes (e.g., elastase) (Fig. 1). 6 An additional microbicidal pathway has also been identified-the neutrophil extracellular trap (NET). Neutrophils extrude NETs composed of a chromatin meshwork containing antimicrobial proteins, and these NETs ensnare and kill extracellular bacteria. 7 It remains to be determined whether NETs are useful host defense mechanisms against motile microbes in the dynamic and unstructured liquid-filled air spaces of the infected lung.

Four different endemic coronaviruses (eCoVs) are etiologic agents for the seasonal "common cold," and these eCoVs share extensive sequence homology with human severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Here, we show that individuals with as compared to without a relatively recent documented eCoV were tested at greater frequency for respiratory infections but had similar rate of SARS-CoV-2 acquisition. Importantly, the patients with a previously detected eCoV had less severe coronavirus disease-2019 (COVID-19) illness. Our observations suggest that pre-existing immune responses against endemic human coronaviruses can mitigate disease manifestations from SARS-CoV-2 infection.

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Sepsis, the systemic inflammatory response to infection, is a leading cause of morbidity and mortality. The mechanisms of sepsis pathophysiology remain obscure but are likely to involve a complex interplay between mediators of the inflammatory and coagulation pathways. An improved understanding of these mechanisms should provide an important foundation for developing novel therapies. In this study, we show that sepsis is associated with a time-dependent increase in circulating levels of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) in animal and human models of sepsis. Adenovirus-mediated overexpression of soluble Flt-1 (sFlt-1) in a mouse model of endotoxemia attenuated the rise in VEGF and PlGF levels and blocked the effect of endotoxemia on cardiac function, vascular permeability, and mortality. Similarly, in a cecal ligation puncture (CLP) model, adenovirus–sFlt-1 protected against cardiac dysfunction and mortality. When administered in a therapeutic regimen beginning 1 h after the onset of endotoxemia or CLP, sFlt peptide resulted in marked improvement in cardiac physiology and survival. Systemic administration of antibodies against the transmembrane receptor Flk-1 but not Flt-1 protected against sepsis mortality. Adenovirus-mediated overexpression of VEGF but not PlGF exacerbated the lipopolysaccharide-mediated toxic effects. Together, these data support a pathophysiological role for VEGF in mediating the sepsis phenotype.

Acute lung injury (ALI) is an inflammatory disease with a high mortality rate. Although typically seen in individuals with sepsis, ALI is also a major complication in severe acute pancreatitis (SAP). The pathophysiology of SAP-associated ALI is poorly understood, but elevated serum levels of IL-6 is a reliable marker for disease severity. Here, we used a mouse model of acute pancreatitis-associated (AP-associated) ALI to determine the role of IL-6 in ALI lethality. Il6-deficient mice had a lower death rate compared with wild-type mice with AP, while mice injected with IL-6 were more likely to develop lethal ALI. We found that inflammation-associated NF-κB induced myeloid cell secretion of IL-6, and the effects of secreted IL-6 were mediated by complexation with soluble IL-6 receptor, a process known as trans-signaling. IL-6 trans-signaling stimulated phosphorylation of STAT3 and production of the neutrophil attractant CXCL1 in pancreatic acinar cells. Examination of human samples revealed expression of IL-6 in combination with soluble IL-6 receptor was a reliable predictor of ALI in SAP. These results demonstrate that IL-6 trans-signaling is an essential mediator of ALI in SAP across species and suggest that therapeutic inhibition of IL-6 may prevent SAP-associated ALI. IntroductionAcute pancreatitis (AP) accounts for more than 220,000 hospital admissions in the United States each year. Risk factors for AP include gallstones and excessive alcohol use. Interestingly, 70%-80% of AP patients develop mild and uncomplicated AP, while 20%-30% will develop more severe symptoms with concomitant multiple organ failure (MOF) (1). MOF is a consequence of the systemic activation of the immune system, known as systemic inflammatory response syndrome (SIRS). The clinical and pathological features of SIRS mimic those of sepsis; however, efforts to identify any infecting organisms in many patients with SIRS have failed (2-4). Although this syndrome is typically seen in individuals with sepsis, SIRS also occurs in patients with severe AP (SAP), blunt trauma, aseptic burns, and widespread surgical manipulations (5, 6). A major complication during SAP is acute lung injury (ALI). Nevertheless, the clinical course of ALI in SAP is still unpredictable and has a mortality rate of up to 50%. Current therapeutic approaches in SAP and associated ALI are symptomatically based (1, 7).The pathophysiology of SAP with ALI is poorly understood. Researchers have long hypothesized that SAP results from activation of digestive enzymes within the pancreas, a process called autodigestion (8). Indeed, inherited mutations in genes encoding for digestive enzymes have been found in patients with a hereditary form of pancreatitis. However, all these patients develop chronic pancreatitis, rather than SAP with ALI (9, 10). Therefore,