Tuberculosis (TB) is one of the oldest known human diseases and is transmitted by the bacteria Mycobacterium tuberculosis (Mtb). TB has a rich history with evidence of TB infections dating back to 5,800 b.c. TB is unique in its ability to remain latent in an individual for decades, with the possibility of later reactivation, causing widespread systemic symptoms. Currently, it is estimated that more than one-third of the world’s population (~2 billion people) are infected with Mtb. Prolonged periods of therapy and complexity of treatment regimens, especially in active infection, have led to poor compliance in patients being treated for TB. Therefore, it is vitally important to have a thorough knowledge of the pathophysiology of Mtb to understand the disease progression, as well as to develop novel diagnostic tests and treatments. Alveolar macrophages represent both the primary host cell and the first line of defense against the Mtb infection. Apoptosis and autophagy of macrophages play a vital role in the pathogenesis and also in the host defense against Mtb. This review will outline the role of these two cellular processes in defense against Mtb with particular emphasis on innate immunity and explore developing therapies aimed at altering host responses to the disease.

One of the early events in the progression of LPS-mediated acute lung injury in mice is the disruption of the pulmonary endothelial barrier resulting in lung edema. However, the molecular mechanisms by which the endothelial barrier becomes compromised remain unresolved. The SRY (sex-determining region on the Y chromosome)–related high-mobility group box (Sox) group F family member, SOX18, is a barrier-protective protein through its ability to increase the expression of the tight junction protein CLDN5. Thus, the purpose of this study was to determine if downregulation of the SOX18-CLDN5 axis plays a role in the pulmonary endothelial barrier disruption associated with LPS exposure. Our data indicate that both SOX18 and CLDN5 expression is decreased in two models of in vivo LPS exposure (intraperitoneal, intratracheal). A similar downregulation was observed in cultured human lung microvascular endothelial cells (HLMVECs) exposed to LPS. SOX18 overexpression in HLMVECs or in the mouse lung attenuated the LPS-mediated vascular barrier disruption. Conversely, reduced CLDN5 expression (siRNA) reduced the HLMVEC barrier-protective effects of SOX18 overexpression. The mechanism by which LPS decreases SOX18 expression was identified as transcriptional repression through binding of NF-κB (p65) to a SOX18 promoter sequence located between −1,082 and −1,073 bp with peroxynitrite contributing to LPS-mediated NF-κB activation. We conclude that NF-κB–dependent decreases in the SOX18-CLDN5 axis are essentially involved in the disruption of human endothelial cell barrier integrity associated with LPS-mediated acute lung injury.

Aims: Exposure to irritant gases, such as bromine (Br2), poses an environmental and occupational hazard that result in severe lung and systemic injury. However, the mechanism(s) of Br2 toxicity and the therapeutic responses required to mitigate lung damage are not known. Previously, it was demonstrated that Br2 up-regulates the heme-degrading enzyme, heme oxygenase-1 (HO-1). Since heme is a major inducer of HO-1, we determined whether an increase in heme and heme-dependent oxidative injury underlies the pathogenesis of Br2 toxicity. Results: C57BL/6 mice were exposed to Br2 gas (600 ppm, 30 min) and returned to room air. Thirty minutes post exposure, mice were injected intraperitoneally with a single dose of the heme-scavenging protein, hemopexin (Hx) (3 µg/gm body weight), or saline. Twenty-four hours post exposure, saline-treated mice had elevated total heme in bronchial alveolar lavage fluid (BALF) and plasma and acute lung injury (ALI) culminating in 80% mortality after 10 days. Hx treatment significantly lowered heme, decreased evidence of ALI (lower protein and inflammatory cells in BALF, lower lung wet to dry weight ratios, and decreased airway hyper-reactivity to methacholine), and reduced mortality. In addition, Br2 caused more severe ALI and mortality in mice with HO-1 gene deletion (HO-1-/-) as compared to wild-type controls, while transgenic mice over-expressing the human HO-1 gene (hHO-1) showed significant protection. Innovation: This is the first study delineating the role of heme in ALI caused by Br2. Conclusion: The data suggest that attenuating heme may prove a useful adjuvant therapy to treat patients with ALI.

Pulmonary fibrosis and emphysema are irreversible chronic events after inhalation injury. However, the mechanism(s) involved in their development remain poorly understood. Higher levels of plasma and lung heme have been recorded in acute lung injury associated with several insults. Here, we provide the molecular basis for heme-induced chronic lung injury. We found elevated plasma heme in chronic obstructive pulmonary disease (COPD) (GOLD stage 4) patients and also in a ferret model of COPD secondary to chronic cigarette smoke inhalation. Next, we developed a rodent model of chronic lung injury, where we exposed C57BL/6 mice to the halogen gas, bromine (Br ₂ ) (400 ppm, 30 minutes), and returned them to room air resulting in combined airway fibrosis and emphysematous phenotype, as indicated by high collagen deposition in the peribronchial spaces, increased lung hydroxyproline concentrations, and alveolar septal damage. These mice also had elevated pulmonary endoplasmic reticulum (ER) stress as seen in COPD patients; the pharmacological or genetic diminution of ER stress in mice attenuated Br ₂ -induced lung changes. Finally, treating mice with the heme-scavenging protein, hemopexin, reduced plasma heme, ER stress, airway fibrosis, and emphysema. This is the first study to our knowledge to report elevated heme in COPD patients and establishes heme scavenging as a potential therapy after inhalation injury.

Nanotechnology has shown great promise for researchers to develop efficient nanocarriers for better therapy, imaging, and sustained release of drugs.

Acute lung injury (ALI) is a life threatening condition associated with hypoxemia, diffuse alveolar damage, inflammation, and loss of lung function. Lipopolysaccharide (LPS; endotoxin) from the outer membrane of Gram-negative bacteria is a major virulence factor involved in the development of ALI. The depletion of glutathione (GSH), an essential intra- and extra-cellular protective antioxidant, by LPS is an important event that contributes to the elevation in reactive oxygen species. Whether restoring GSH homeostasis can effectively ameliorate mitochondrial dysfunction and cellular apoptosis in ALI is unknown and therefore, was the focus of this study. In peripheral lung tissue of LPS-treated mice, hydrogen peroxide and protein nitration levels were significantly increased. Pre-treatment with GSH-ethyl ester (GSH-EE) prevented this increase in oxidative stress. LPS also increased the lactate/pyruvate ratio, attenuated SOD2 protein levels, and decreased ATP levels in the mouse lung indicative of mitochondrial dysfunction. Again, GSH-EE treatment preserved the mitochondrial function. Finally, our studies showed that LPS induced an increase in the mitochondrial translocation of Bax, caspase 3 activation, and nuclear DNA fragmentation and these parameters were all prevented with GSH-EE. Thus, this study suggests that GSH-EE supplementation may reduce the mitochondrial dysfunction associated with ALI.