Introduction: A small clinical trial showed HAT therapy improved survival but no studies have been reported in animal models to examine potential mechanisms. Methods: Sepsis was induced in female mice using the cecal ligation and puncture (CLP) model. Physiologic parameters including heart rate (HR), pulse distension (PD), and respiratory rate (RR) were measured noninvasively at baseline, 6 and 24 h post CLP. These measurements stratified mice into predicted to live (Live-P) or die (Die-P). Mice were randomized to receive HAT therapy or vehicle. Oxidative stress was measured in peritoneal exudative cells 24 h after CLP. Results: HR, PD, and RR all declined within the first 6 h of sepsis and were significantly lower in the Die-P mice compared with Live-P. HR 6 h post-CLP best predicted mortality and continued to decline between 6 and 24 h post CLP. Oxidative stress in peritoneal cells harvested 24 h post CLP (determined by 8 isoprostaglandin F2α and protein carbonyl derivatives) was significantly higher in the Die-P mice. HAT therapy was initiated 7 h post-CLP after mortality prediction and stratification. HAT significantly reduced oxidative stress in the Die-P mice without altering these parameters in the Live-P mice. HAT treatment prevented the decline in HR, again only in the Die-P mice. Mice treated with HAT therapy had significantly better survival. Conclusions: Physiologic parameters accurately predicted mortality. Die-P mice had significant oxidative stress compared with Live-P. HAT therapy significantly decreased oxidative stress, increased HR, and improved survival in the Die-P mice. These data suggest that HAT exerts a beneficial effect through reducing oxidative stress and improving cardiovascular function.

Particulate matter heavily pollutes the urban atmosphere, and several studies show a link between increased ambient particulate air pollution and exacerbation of pre-existing pulmonary diseases, including asthma. We investigated how diesel exhaust particulates (DEPs) aggravate asthma-like pulmonary inflammation in a mouse model of asthma induced by a house dust extract (HDE) containing cockroach allergens and endotoxin. BALB/c mice were exposed to three pulmonary challenges via hypopharyngeal administration of an HDE collected from the home of an asthmatic child. One hour before each pulmonary challenge, mice were exposed to DEP or PBS. Pulmonary inflammation was assessed by histological features, oxidative stress, respiratory physiological features, inflammatory cell recruitment, and local CXC chemokine production. To prove the role of CXC chemokines in the augmented inflammation, CXC chemokine-specific antibodies were delivered to the lungs before DEP exposure. DEP exacerbated HDE-induced airway inflammation, with increased airway mucus production, oxidative stress, inflammatory cell infiltration, bronchoalveolar lavage concentrations of CXC chemokines, and airway hyperreactivity. Neutralization of airway keratinocyte-derived chemokine and macrophage inflammatory protein-2 significantly improves the respiratory function in addition to decreasing the infiltration of neutrophils and eosinophils. Blocking the chemokines also decreased airway mucus production. These results demonstrate that DEP exacerbates airway inflammation induced by allergen through increased pulmonary expression of the CXC chemokines (keratinocyte-derived chemokine and macrophage inflammatory protein-2).

Background: ''Cytokine storm'' has been used to implicate increased cytokine levels in the pathogenesis of serious clinical conditions. Similarities with Severe Acute Respiratory Syndrome Coronoavirus-2 (SARS CoV-2) and the 2012 Middle Eastern Respiratory Syndrome led early investigators to suspect a ''cytokine storm'' resulting in an unregulated inflammatory response associated with the significant morbidity and mortality induced by SARS CoV-2. The threshold of blood cytokines necessary to qualify as a ''cytokine storm'' has yet to be defined. Methods: A literature review was conducted to identify cytokine levels released during 11 assorted clinical conditions or diseases. Weighted averages for various cytokines were calculated by multiplying the number of patients in the paper by the average concentration of each cytokine. Correlation between cytokine levels for individual conditions or diseases were assessed using Pearson correlation coefficient. Results: The literature was reviewed to determine blood levels of cytokines in a wide variety of clinical conditions. These conditions ranged from exercise and autoimmune disease to septic shock and therapy with chimeric antigen receptor T cells. The most frequently measured cytokine was IL-6 which ranged from 24,123 pg/mL in septic shock to 11 pg/mL after exercise. In patients with severe SARS CoV-2 infections, blood levels of IL-6 were only 43 pg/mL, nearly three magnitudes lower than IL-6 levels in patients with septic shock. The clinical presentations of these different diseases do not correlate with blood levels of cytokines. Additionally, there is poor correlation between the concentrations of different cytokines among the different diseases. Specifically, blood levels of IL-6 did not correlate with levels of IL-8, IL-10, or TNF. Septic shock had the highest concentrations of cytokines, yet multiple cytokine inhibitors have failed to demonstrate improved outcomes in multiple clinical trials. Patients with autoimmune diseases have very low blood levels of cytokines (rheumatoid arthritis, IL-6 ¼ 34 pg/mL; Crohn's disease, IL-6 ¼ 5 pg/mL), yet respond dramatically to cytokine inhibitors. Conclusion: The misleading term ''cytokine storm'' implies increased blood levels of cytokines are responsible for a grave clinical condition. Not all inflammatory conditions resulting in worsened disease states are correlated with significantly elevated cytokine levels, despite an association with the term ''cytokine storm''. ''Cytokine storm'' should be removed from the medical lexicon since it does not reflect the mediators driving the disease nor does it predict which diseases will respond to cytokine inhibitors.

Neutrophils play a critical role in the eradication of pathogenic organisms, particularly bacteria. However, in the septic patient the prolonged activation and accumulation of neutrophils may augment tissue and organ injury. This review discusses the different activation states and chemotaxis of neutrophils in septic patients. Neutrophil killing of bacteria and the formation of neutrophil extracellular traps represent important components of the innate immune response and they become dysregulated during sepsis, possibly through changes in their metabolism. Delayed neutrophil apoptosis may contribute to organ injury, or allow better clearance of pathogens. Neutrophils provide a friendly immune response to clear infections, but excessive activation and recruitment has the potential to turn them into potent foes.