Hyaluronan and halogen‐induced airway hyperresponsiveness and lung injury

Abstract

Chlorine (Cl 2) and bromine (Br 2) are produced in large quantities throughout the world and used in the industry and the sanitation of water. These halogens can pose a significant threat to public health when released into the atmosphere during transportation and industrial accidents, or as acts of terrorism. In this review, we discuss the evidence showing that the activity of Cl 2 and Br 2 , and of products formed by their interaction with biomolecules, fragment high-molecular-weight hyaluronan (HMW-HA), a key component of the interstitial space and present in epithelial cells, to form proinflammatory, low-molecular-weight hyaluronan fragments that increase intracellular calcium (Ca 2+) and activate RAS homolog family member A (RhoA) in airway smooth muscle and epithelial and microvascular cells. These changes result in airway hyperresponsiveness (AHR) to methacholine and increase epithelial and microvascular permeability. The increase in intracellular Ca 2+ is the result of the activation of the calcium-sensing receptor by Cl 2 , Br 2 , and their by-products. Posthalogen administration of a commercially available form of HMW-HA to mice and to airway cells in vitro reverses the increase of Ca 2+ and the activation of RhoA, and restores AHR to near-normal levels of airway function. These data have established the potential of HMW-HA to be a countermeasure against Cl 2 and Br 2 toxicity.

Chitinase 3-like-1 protects airway function despite promoting type 2 inflammation during fungal-associated allergic airway inflammation

“…BRP-39 can also bind to collagen (2) and other endogenous ligands including hyaluronan (62), leaving open the possibility of multiple potential nonimmune functions of secreted BRP-39. Recent studies suggest that low molecular weight hyaluronan fragments can drive AHR, whereas high molecular weight hyaluronan fragments can reduce AHR (63,64). Although speculative, the absence of BRP-39 may result in hyaluronan-mediated events during fungal asthma that negatively affect AHR.…”

Low Molecular Weight Hyaluronan Inhibits Lung Epithelial Ion Channels by Activating the Calcium-Sensing Receptor

“…HMW-HA interacts through hydrogen bonds, van der Waals, and electrostatic forces with specific proteins called hyaladherins and with membrane receptors, modulating development, morphogenesis, cell migration, apoptosis, cell survival, inflammation, and tumorigenesis [53]. It protects from ozone [32], and bleomycin injury [54,55], smoke inhalation [56][57][58], sepsis [59,60], and halogens inhalation toxicity [19,61]. The breakdown of HMW-HA by hyaluronidases or reactive oxygen species generate smaller fragments of low molecular weight of less than 500 kDa that, by contrast to HMW-HA, promote inflammation, angiogenesis, epithelial to mesenchymal cell transition [62][63][64][65][66], and tissue injury [67,68].…”

“…The expression of the Ca-SR in the respiratory system plays an important role in fetal lung growth and development by stimulating fluid secretion in the pulmonary lumen [78,79], lung branching, and morphogenesis in mice [80]. Ca-SR is expressed in human and mouse airway smooth muscle cells and bronchiolar epithelial cells [81], and its expression was increased in the vascular airway smooth muscle of patients with PAH [82,83], asthma [25,81,84], allergen-sensitized mice [81], and in mice exposed to toxic chemicals such as chlorine and bromine [19,20]. Degradation of hyaluronan and its accumulation in the distal lung following injury was associated with edema formation [4,5] because of its ability to attract and retain water.…”

“…In two studies, it was found to inhibit the pain sensitive channel TRPV1 [16], and reduce the open probability of a stretch-activated ion channel heterologously expressed in Xenopus oocytes [17]. LMW-HA was found to induce lung hyper-reactivity by increasing Cai 2+ in airways smooth muscles through the activation of G-protein coupled CaSR [18][19][20].…”

Halogen exposure injury in the developing lung

“…[31][32][33][34] The epidemiology and pathophysiology of halogen exposure toxicity in general, nonpediatric population is reviewed in great detail in the accompanying review by Lazrak et al in this issue. 35 We focus our discussion on the effects of halogen exposure on the developing lung as it may pertain to neonates, infants, toddlers, and young children and will compare the pathological changes with those that are observed in the fully developed lung.…”