Mucociliary Dysfunction in HIV & Smoked Substance Abuse

Impaired mucociliary clearance (MCC) is a hallmark of acquired chronic airway diseases like chronic bronchitis associated with chronic obstructive pulmonary disease (COPD) and asthma. This manifests as microbial colonization of the lung consequently leading to recurrent respiratory infections. 

People living with HIV demonstrate increased incidence of these chronic airway diseases. Bacterial pneumonia continues to be an important comorbidity in people living with HIV even though anti-retroviral therapy has succeeded in restoring CD4+ cell counts. People living with HIV demonstrate increased microbial colonization of the lower airways. The microbial flora is similar to that observed in diseases like cystic fibrosis and COPD suggesting that mucociliary dysfunction could be a contributing factor to the increased incidence of chronic airway diseases in people living with HIV. 

The three principal components of the MCC apparatus are, a mucus layer, ciliary beating, and a periciliary airway surface liquid (ASL) layer that facilitates ciliary beating. Cystic fibrosis transmembrane conductance regulator (CFTR) plays a pivotal role in regulating the periciliary ASL. HIV proteins can suppress all the components of the MCC apparatus by increasing mucus secretion and suppressing CFTR function. This can decrease ASL height leading to suppressed ciliary beating. The effects of HIV on MCC are exacerbated when combined with other aggravating factors like smoking or inhaled substance abuse, which by themselves can suppress one or more components of the MCC system. 

This review discusses the pathophysiological mechanisms that lead to MCC suppression in people living with HIV who also smoke tobacco or abuse illicit drugs.

Below:  (A) HIV Tat induces expression of TGF-β1 mRNA with a concomitant decrease in CFTR mRNA levels. NHBE ALI cultures re-differentiated at the air liquid interface were treated with recombinant Clade B Tat (10 nM: *p < 0.05) apically and basolaterally. Total RNA was isolated and TGF-β1 and CFTR mRNA levels were quantitated by qRT-PCR. HIV Tat induces almost a 1.7-fold increase in TGF-β1 mRNA expression. This translates to a significant decrease in CFTR mRNA levels. Data are mean ± SE of three experiments from three different lungs. (B) Nationwide trends in Cigarette smoking and drug abuse in general population compared with people living with HIV. While the trend in addiction is similar between the two, the proportion of people living with HIV who smoke cigarettes or abuse street drugs is significantly than that observed in the general population. Cigarette smoking is the most prevalent addiction [62.5% smokers (Benard et al., 2007; Lifson et al., 2010; Lifson and Lando, 2012) compared to 17.8% nationwide], followed by Marijuana [29% (Woolridge et al., 2005) compared to 7.5% nationwide], Cocaine [22.5% (Hinkin et al.,2004) compared to 0.6% nationwide] and methamphetamine [11% (Mitchell et al., 2006) compared to 0.2% nationwide]. The data for substance abuse in the general population is obtained from http://www.drugabuse.gov/national-survey-drug-use-health.

Below:  Schematic model of HIV and substance abuse induced Mucociliary dysfunction. HIV Tat and Cigarette smoke can inhibit CFTR biogenesis and function. HIV Tat increases TGF-β1 mRNA levels with a corresponding decrease in CFTR mRNA. Cigarette smoke can suppress CFTR biogenesis by TGF-β1 signaling or directly inhibit CFTR function by trapping surface CFTR in aggregosomes. Cigarette smoke, marijuana and cocaine can also inhibit the Ciliary component of MCC by decreasing CBF or ciliostasis (by cocaine). Marijuana smoking can lead to a loss of ciliated cells in the airway epithelium. The effects of these drugs on the ciliary component can synergize with the effects of HIV Tat mediated suppression of CFTR leading to a pronounced suppression of MCC. A combination of HIV gp120, Cigarette smoke and/or Marijuana can also promote mucus hypersecretion in the milieu where CFTR function is already attenuated by Tat and cigarette smoke leading to Dysregulation of all the principal components of the MCC system. Dysregulation of one or more components of the MCC system will lead to mucus impaction and microbial colonization. Pharmaceutical drugs that increase intracellular cAMP by either activating cyclase or inhibiting phosphodiesterase when used in combination with CFTR potentiators like Ivacaftor can restore one or more components of the MCC and repair the mucociliary dysfunction.

Full article at:  http://goo.gl/q4vIqB

By: Srinivasan Chinnapaiyan and Hoshang J. Unwalla^*

Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA

Edited by: Pankaj Seth, National Brain Research Centre, India

Reviewed by: Hidekatsu Iha, Oita University, Japan; Yoshitaka Sato, Nagoya University Graduate School of Medicine, Japan

*Correspondence: Hoshang J. Unwalla, Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, 11200 SW 8th Street, AHC-1 #421, Miami, FL 33199, USA ; Email: ude.uif@allawnuh

  

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